Multiple Sclerosis Discovery: The Podcast of the MS Discovery Forum

[intro music]

Host – Dan Keller

Hello, and welcome to Episode Ninety-eight of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller.

Today's interview again features Dr. David Baker, Professor of Neuroimmunology at Queen Mary University of London in the U.K. We spoke at the ECTRIMS conference last fall. In part one of our interview he raised the issue of why there has been very poor translation from animal models to clinical trials. Today, Dr. Baker, also known as the ”Mouse Doctor” for his work with animal models, lays out why this situation exists and what to do about it.

Interviewee – David Baker

I think there’s many reasons why, and I think we all have our failings. And one can point the finger at the animal models, which a lot of the clinicians do, saying it’s the animal model’s fault, which is possible. But I think also we have to look at humans and how humans use their animal models. And then how humans translate the data from the animal models into the clinic, because I think there’s many failings along the line, and I think that’s one of the reasons for the failing between the two.

I think one of the failings is, in terms of the animal models, that when we do our animal models for these, we’re looking for mechanisms not treatments. And so about 70% of studies give drug before disease is ever induced, which never happens in a human. You know, you go after you’ve had one or two or more attacks before you’re given drugs. We also use the drugs in a way that are never used in a human, so people will do what they call a prophylactic drug where they’ll give it before the disease manifests itself. Or a therapeutic dose, which is probably when the animals are showing their symptoms. But in reality, a human would be getting steroids at that time point. They would never get a DMT. So you’re not comparing, you know, apples with apples. You’re comparing apples with pears, and I think that’s one of the problems.

And I think, you know, if you try and block an immune response from being generated, that’s quite easy compared to stopping an immune response once it’s been generated, because immunity’s about giving life-long protection against infections. And so I think it’s a different type of beast to target. So I think this is where the animal models could do it, because EAE is one of the few where you have this relapsing-remitting disease course. But it’s very, very rare that people actually start to treat in between attacks to block further relapses. I think that’s one of the problems.

The other big problem is the dose; the dose relationship between animals and humans. There’s a tendency we just keep giving more and more and more and more, and eventually the drugs will work. But you’ve got this problem that animals are very liable to be stressed, and we call it the building site effect, so construction site effect. And if you have lots of loud noises, it scares animals. They get very stressed, and your EAE just disappears. And likewise, if you just give lots and lots of drug, that probably tastes nasty. They get stressed out as well. And I think many of the so-called wonder cures – cures of the week – are because we’re just giving too much, which doesn’t have a relationship to what the human dose is going to be.

And then, likewise, I think we’ve got too much of a publication bias for the need to generate positive data. And I think what we then have to do is we have to look at the quality of the data. And I think there has been a lot of failure to replicate data. I think some of that is because some studies lack quality control, and the way I look at that – and I could be wrong; obviously it’s an opinion – but if you look at the way that EAE is scored (it’s normally a scoring system 1 to 3 or 1 to 4) and then you have your drug, which may be, you know, takes your control down from 3 down to a 1. But then, every now again, you look at the studies where it goes either way, and your controls are at 1 and it goes up to 3, and I ask the question how do you get a score of 1? Because if you had four animals, they’re all scoring 1. Or is it three animals score 0 and one score 4, and that will give you a score of 1. And I think if people were made to actually put the data about how many animals got disease, we’d be able to interpret those line graphs. Because I feel that, in many cases, some of those graphs lack quality control.

If you have a robust quality control system, your control group should be giving you roughly the same type of scores every time. But in individual papers you can see, in some groups you have a score of 1 in the control group. The next experiment it’s a score of 3. To my mind I think if you look at that, then those are probably the experiments are much more likely not to replicate. So I think you have to be, obviously, skeptical, but I really would like people to actually probably give us the information about how many animals got disease – what is their mean score – in addition to those line graphs. Because without that, they’re impossible to interpret.

So that’s, you know, kind of one problem of the animals. And then for the humans, you have the same problems. So they over-interpret the animal data. The people doing the clinical trials are very, very rarely the people who came up with the idea. So if there’s a weird side effect that you may know about, you know, that’s not translated to the person who’s actually doing the study, because they don’t talk to the basic scientists. Then they probably underpower the studies. They don’t necessarily pick the right outcome measurements. So I think there’s many failings in both sides of the equation, and it’s not always the animal model. But I think unless we kind of up our game, I think it’s going to be very difficult for the people who are working on animal models, because you know, there are treatments that come along for, you know, the immune part of multiple sclerosis.

And if you’re thinking about the ethical use of animals, it’s much harder to make the ethical argument that you should be using disease models which are very severe for the animals to try and work out fundamental parts of biology. And, therefore, I think we’ll find that you know the funding agencies start to say, well, why are we funding this work? So I think we need to have good quality work, because if we don’t have good quality work, it allows that clinical view that animal work doesn’t really deliver the treatments. And I think they can deliver the treatments, but we just have to use our animal studies wisely to ask questions rather than, you know, blindly saying this will work in multiple sclerosis because it works in EAE. That doesn’t make sense to me.

Interviewer – Dan Keller

Do you have any succinct tips for people who are either reviewing papers on animal studies or people who are reading those papers once they’re published or even the general public reading a news story?

Dr. Baker

Well my first tip would be probably – and this is okay as an opinion – but, you know, EAE data is nonparametric. It goes 1, 2, 3, 4; it’s not a continuous scale, so first tip is don’t use, you know, the t-test of parametric data on nonparametric data. And that does make a difference. There is a Nature paper published this year that was analyzed with a t-test. If you analyze it with a Mann-Whitney test, which you should have done, the data becomes nonsignificant. So rather than the take home message is, you know, this is a new wonder drug for multiple sclerosis, their answer should have been you have to go back and reproduce your EAE experiment because it didn’t work. So I think that would be the first tip. And then the second tip, I would really like people to say, tell us how many animals get disease and on what level and when, so we can interpret the line graph.

MSDF

This is something that you routinely see in oncology done right. They talk about percent of responders, and among responders, what was the shrinkage of the tumor? They don’t average it out among all the people who dilute it out by not responding.

Dr. Baker

Well I think one of the problems as well is we’ve also got this publication bias. We’ve got you know this urge to see positive data, and I think that skews the whole system.

MSDF

Has anything changed since you came out with a response to the animal checklist?

Dr. Baker

I think, sadly, no, but we’re actually doing the checklist again, so we will be able to see if things have changed. I don’t think it has. I think the message hasn’t gotten through. But I think – this is, again, another one of those nails in the animal model coffin that, if we don’t up our game, we’ll be seen to be doing an inferior quality work and eventually we’ll get discarded. So I know that some of the grant councils are, as you know, saying this is a condition of your grant. But I think you know it’s been slow to change, and I think one of the reasons is actually people who are leaders of the field actually are some of the people who are some of the worst offenders. So we’re leading by bad example rather than good example.

MSDF

We don’t want to leave the listener with the impression that you’re against animal models. I mean, you’re known as “Dr. Mouse,” so you know I guess you just want to see them done well.

Dr. Baker

Yes, I’m passionate. I mean, I really you know believe animal models have a real positive impact to do. And I’ve been really lucky in the recent years is that, you know, some of those animal models – and work we’ve done from animal models – is going through into humans and you know is starting to make the difference. So you know our work with the Cannabis was great. You know, it shows that you know our animal work has validity. Without the animal model stuff we’ll never really understand the biology. You can’t do all the experiments in humans. You do need experimental systems to be able to ask questions. And you need to be able to invent.

And you know there is some fantastic work. You know I’ve picked up the papers, and I get really excited by it, but I think, at the same time, we have to also be a drum to say, you know, try and improve the quality. Because, at the end of the day, it’s more likely that if you’re doing good quality animal experiments, that other people will be able to replicate it. And it will move the field on further and faster. And I think if people believe what we produce as being good solid work, then it’s going to be a win-win situation.

MSDF

It would be nice to see sort of a meta-analysis of animal studies that are considered to have been done well versus those not and see which ones translated into advances in the human situation, because so many times they say, well, sure it works in animals, but it doesn’t work in humans. Well if it works in animals because it was set up not so well, then that might be a reason not to work in humans.

Dr. Baker

Yes. I think you know the problem of animal models has got nothing peculiar to the multiple sclerosis field. It’s just a common theme. And I think that tells me it’s not a problem of animal models, because if it’s so common in every other discipline, it tells us it’s something how we use the animals is the fundamental problem. Now, you know for MS, we don’t really know. I mean, I think this going to be the – we’re at ECTRIMS now, and I think the whole world can change a little bit today, or in the next few days, because we’ve always thought of MS as being a T cell-mediated disease. Now that may be still the true answer, but now we’re starting to see ocrelizumab, which is a big B cell depleting antibody probably – I’m predicting – to have as good an effect as anything that the T cell you know brigade has ever done. And, in fact, if you look at most of the MS drugs, you would say that most of them actually are inhibiting B cell function.

Now, does that tell us that B cells are driving the disease? It may well do. Or it may well not. Now some people could argue – and they will – you know they’re the reservoir for the virus that causes multiple sclerosis. And then other people will say, well, actually the antigen-presenting cells. And let’s see, but I think what we’ll find is you know EAE will have to have changed its focus. We’ve been focusing our studies on T cell biology, but in fact, the T cell-inhibitory molecules haven’t really delivered. So is that right? And it may well be you know we have to think of a different biology. But EAE can certainly do that if need be.

So we’ll have to you know try and work out how do these B cell-depleting agents work. Is it you know via antigen presentation or not? I don’t know.

MSDF

We’ve always thought of T cells as regulating B cells. Now it looks like they both regulate each other.

Dr. Baker

I mean, I have my history in skin diseases, and when I first started working, actually my boss was more interested in B-regulatory cells. T-regulatory cells kind of hadn’t really existed at that time point. So I think we’re trying to reinvent the wheel. If we look throughout the literature, it’s a cross-talk between T and B cells are probably the answer. And we’ll see. Again, from our animal studies, we’ve had animal studies where we’ve manipulated the immune system making sure that has a positive effect. We’ve been able to translate that, so we have an N of 1 where we’ve got rid of somebody’s neutralizing beta-interferon antibodies by antigen-specific mechanisms. Now if we could translate that into MS, then we may have a way of treating MS. But we’ll see.

MSDF

Very good, thank you. I appreciate it.

Dr. Baker

Okay.

[transition music]

MSDF

Thank you for listening to Episode Ninety-eight of Multiple Sclerosis Discovery. This episode is the final one in our series of MS podcasts. We hope that the series has been enlightening and has spurred further discussion about the causes of MS and related conditions, their pathological mechanisms, potential ways to intervene, and new research directions. We’ve tried to communicate this information in a way that builds bridges among different disciplines, with a goal of opening new routes toward significant clinical advances. Although we won’t be adding any new podcasts, the series will remain available on the MS Discovery website for the foreseeable future.

This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. Msdiscovery.org is part of the nonprofit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is Vice President of Scientific Operations.

[outro music]

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

For Multiple Sclerosis Discovery, I'm Dan Keller.

[intro music]

Host – Dan Keller

Hello, and welcome to Episode Ninety-seven of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller.

Today's interview features Dr. David Baker, Professor of Neuroimmunology at Queen Mary University of London in the UK. We spoke at the ECTRIMS conference last fall, where I asked him about his work with cannabinoid compounds – work that has led to a better understanding of the cannabinoid system as well as to candidate drug compounds to treat spasticity.

Interviewer – Dan Keller

In terms of what you're doing now with cannabinoids, can you tell me what you are looking for, and what you've found?

Interviewee – David Baker

Many, many years ago, we actually were probably the first people to show that cannabis can actually alleviate muscle stiffness in animal models of multiple sclerosis, which then kind of underpinned the push to look for cannabis in MS. So people with MS were smoking cannabis and perceiving benefit. The question was, why? And what they didn't really understand that there was going to be an unfolding biology. And a few years later after our first discovery that actually cannabinoids can cause relaxation of the muscles, we understood that the function of the cannabinoid system is to regulate nerve signaling. And so because the cannabinoid system does regulate the strength of synaptic signaling, then it's obvious that it can inhibit signs and symptoms because of this excessive neurostimulation. So at the time of that, then we realized that the receptor is a CB1 receptor, and the compound within cannabis is THC, and they're the same molecules that cause all the side effects. So you could never really disassociate away the high from the medical benefit. So we started to think, well, how can we try and get the medical benefit from the cannabinoid system and at the same time try and limit the side effect potential.

So what we thought is, well, if we can stop the cannabinoid molecules getting in the brain, then they won't cause the side effects. But maybe we can target the aberrant signaling in the spinal cord and the peripheral system to try and get the benefits. And so that was our intention. So we tried to make a CNS-excluded drug. And that's, in fact, what we did. We made a drug that was very, very water soluble, so you know, you use the mechanism of the blood-brain barrier to actually exclude it from the brain. So we made the compound, and a few weeks later, we kind of started putting it into animal models, not really doing it the pharmaceutical way, which would be a methodical testing. So we showed that it didn't cause any of the unwanted side effects that are associated with cannabis in the animals. And then we put it in a system where we had a spasticity in a multiple sclerosis relevant system, and the drug worked.

Now what we did know is that the drug was blocked by the activity of the CB1 receptor antagonist, so it looked like we'd made what we set out to make. So we were really excited. And from that point, we started to try and see if we could develop it as a drug. Unfortunately what we realized very quickly actually is that it doesn't work by the known cannabinoid receptor system, and I think what we stumbled across is a whole new biology of the cannabinoid system.

And so we've been developing this drug bit by bit. We set up a university spinout company to try and develop it as a pharmaceutical drug. And over the years, bit by bit, we've been pushing it forward. So it's very safe in animals. It has a massive therapeutic window. And with grant funding agencies etc. we've managed to be able to take it into phase I study where it passed with flying colors. We tested it in 60 healthy humans. And a few weeks ago, we started our first testing in people with multiple sclerosis. So we'll have to see how it works. But we hope by early in 2016 we'll have the answer. So it could be a symptom modifying drug, but it doesn't have any of the side effects associated with drugs such as, you know, Sativex or baclofen as well. So it's not sedating as far as we know.

The way that the drug works is a new mechanism. And what we can probably say is it serves to block the excitation of nerves. So it dampens down excessive signaling, which are probably the consequences or the causes of spasms and spasticity and possibly the symptoms as well and maybe pain. We just have to do more work to see if it will work that way.

MSDF

Is this a hyperexcitable system? Or is it a hypoinhibited system where you're getting this spasticity?

Dr. Baker

Well, I think spasticity is largely caused by loss of the inhibitory circuitry. So there's probably less GABAergic signaling. And so one can, you know, drive the inhibitory system, like you do with GABA, but likewise you can actually kind of block the excitation. And this mechanism actually probably only exists in pathology. So this is probably why there isn't the side effect potential that the real target that we're actually after really only occurs when the nervous system is going a bit haywire. So that's why we think we've got good safety margin.

MSDF

And you had told me that this does not induce hunger, which I guess is another sign that it's not getting into the CNS?

Dr. Baker

Having said all that, it was made not to get in the central nervous system, but in reality, it doesn't matter if it does get in the central nervous system. So in fact, about 15% of the drug does get into the central nervous system, which would be as good as many drugs that are CNS penetrant. I guess when we were starting, we were hoping that, you know, it was going to be excluded because we thought it was a cannabinoid receptor agonist, but in reality, it doesn't matter. And in fact what we know is actually this targeting into the lesions. So there's actually more goes into the area. And what this kind of spins on to some other work that we've done with some of our sodium channel work.

We've been developing new sodium channel blockers as potential neuroprotectants. And what we've done is certain molecules actually get excluded by CNS drug pumps, and what we'd noticed in MS is that some of these drug pumps disappear. So we made a drug that was actually targeted specifically to one of those drug pumps, which would normally mean it would be excluded from the brain, but what we showed is that with these new sodium channel blockers, that actually they physically target into the lesion where the pump disappears. And so again, you increase this therapeutic window between effect versus side effect, because again with the sodium channels, you need them for health. You block them, and you have side effects. But what we've found with the sodium channel blockers is that in the animal models, sodium channel blockers were neuroprotective, and we then took that idea forward actually into the clinical trial.

So we first of all thought the trials with sodium channel blockers had failed. Why had they failed? Well, the reason they failed was the trial outcomes weren't right, and suddenly actually because of this unpleasant side effect, 50% of the people didn't take the drug. So the trial was doomed before it ever started. And then what we had was we had the bloods of the people in the trial. So we looked two years after the trial had finished and was seen to be a failure, and we found that 50% of people weren't taking the drugs. But if you look to the people who were taking the drugs, we could see that there was less neurofilament in their blood indicative that there is less nerve damage. And so actually in reality, the trial actually was positive, but it was seen to be negative because of this failure to take the drug.

So the question was, how could we then develop that forward? So the clinical guy said, well, let's think how we could best do a quick trial. And they came up with the idea of the optic nerve being the ideal target. And so what they said to us was, can you, you know, model this in the animal model? So we developed a new animal model. So we took Vijay Kuchroo's 2D2 mice, which are preprogrammed to get optic neuritis, and then we just made their eyes florescent so we could just look in their eyes and see nerves in real time and in life. And as a consequence of using the transgenic, which targeted myelin oligodendrocyte glycoprotein, the cells would go in, cause optic neuritis, that would cause nerve death, and then we could monitor the nerve death just by looking into the eye, because each nerve was labeled with a fluorescent protein. We'd see one single nerve die.

And so we started to use that as a way of testing different drugs for neuroprotection. And we put a whole stack of different compounds, minocycline, sodium channel blockers, glutamate receptor antagonist, we did a few. And we got some hits with the sodium channel blockers, and we tried a few of the different ones, some of them better than others. And unfortunately the one that they chose for the trial is probably the worst one in the animals, but they decided that you had to load drug quickly, so they selected phenytoin. So we showed that the sodium channel could work in the optic neuritis, and then the idea was then we translate that and then do a trial with optic neuritis in the human.

So this was a trial that Raj Kapoor did. And so the idea was that people go blind, and then you go to the doctors. And then they were randomized to either get steroids, which is the standard treatment, or they'd get steroids plus a sodium channel blocker, which was phenytoin at the time. And that was done because you can dose very quickly. So the idea was to get people on drug very quickly. So within seven days of their first symptom, people were on active drug. And people were treated for about six months. And then they looked at the retinal fiber thickness. So as a consequence of the ganglion in the retina dying, the retina thins, and then you can measure that with a machine called OCT, optical coherence tomography. And that was slowed. So they saved 30% of the nerves from dying, even though there were people getting a steroid. So it tells us that really certain channel blockers are neuroprotective.

And then the question is, is how then can we show that in reality? So what we've done from there is we've actually gone on with another sodium channel blocker, which was called oxcarbazepine, which was much more effective in the animal models. And we've been trying to initiate a new trial design whereby we're looking for people who are on current DMTs by showing evidence of neurofilament release, which is indicative that their nerves are being destroyed, because as the nerves are destroyed, they liberate their contents, and then we can pick that up in the biological fluids. So the idea is that if they've got neurofilaments in their cerebrospinal fluid, they get the option of having a sodium channel blocker in addition to their DMT. And then we'll monitor them by serial lumbar punctures to see if the neurofilament levels decrease as a way of a trench push on the trial design for phase II.

Because if you're thinking about the standard phase III, phase II trial for neuroprotection, you're talking about a two- or three-year trial, which will take you two years to recruit the 600 people and another year to do the analysis. So you're really talking about a seven-year trial with 600 people. This trial design will kind of push it down probably to 12 months to 18 months with 60 people. So we can do 10 times more people and a lot quicker this way. So that's started where we've been recruiting, and we're still recruiting, but fingers crossed that would be another way forward in terms of developing neuroprotection. I think it shows how we've been trying to use our animal models to translate things into the human. Because at the end of the day, there has been really, really poor translation between the animal models and humans. And I guess the question is, is why?

MSDF

We’ll pick up on that question in part two of our interview with Dr. Baker next time, when he’ll describe some of the deficiencies he sees in the design and interpretation of animal experiments and how they could be improved to better relate to clinical trials and the clinical situation.

[transition music]

MSDF

Thank you for listening to Episode Ninety-seven of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. Msdiscovery.org is part of the nonprofit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is Vice President of Scientific Operations.

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

[outro music]

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

For Multiple Sclerosis Discovery, I'm Dan Keller.

[intro music]

Host – Dan Keller

Hello, and welcome to Episode Ninety-six of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller.

Today's interview features Drs. Bibiana Bielekova, who is an investigator at the National Institutes of Health, and Mika Komori, a postdoctoral fellow in her lab. We caught up with the two physician-researchers at the ACTRIMS meeting in New Orleans earlier this year. At the meeting, Dr. Komori talked about a new and more sensitive way to evaluate what may be happening in the brains and spinal cords of people with progressive MS.

In a recent study, she examined samples of cerebral spinal fluid, or CSF, collected through a thin needle near the base of the spine. She was scouting for immunological biomarkers of progressive MS. In the analysis, a molecule called CD27, mostly from T cells, stood out, as did another marker specific to B cells. Even more revealing was the ratio of the CD27 molecule to the T cells. T cells are a big player in relapsing MS and not usually associated with the progressive, more neurodegenerative forms of MS. The unexpected results raise new questions about why immune-modulating drugs do not seem to be effective against progressive MS.

If validated, the new test may lead to better diagnosis and treatment of people with MS and other neurological disorders. And it may speed up clinical trials in progressive MS and reduce their cost. In fact, the same research team used their new biomarker test in a small phase 2 study of the anti-B cell drug, rituximab, delivered both intravenously in the blood and intrathecally in the spinal column. Unfortunately, the new biomarker test showed that the double delivery system did not work as expected to eliminate inflammatory B cells trapped in the brains of people with progressive MS. They stopped the study early for lack of efficacy.

In a change to our usual podcast format, Dr. Bielekova interviewed Dr. Komori about the specifics of the study and put the results in a larger context. Midway through the interview, Carol Morton, a past editor of MS Discovery Forum, asked both doctor-scientists about what the new test means for treating patients.

Interviewer – Dr. Bibiana Bielekova

As a physician, when we see patients, we don’t really know what’s happening in their brains, right? We are using some tools that are supposed to help us to identify like, for example, MRI, but they are not perfect. So, how did you choose to address that problem?

Interviewee – Dr. Mika Komori

So, when I saw patients, I can’t tell them that the drug, which are now available, is effective or not, especially for progressive MS patients, because currently so far all big clinical trials, they didn’t show any effects on them. Because of that result, we think progressive MS patients don’t have any intrathecal inflammation. So far we believe MS – multiple sclerosis – is inflammatory disease, but we don’t know if it’s true for progressive MS or not.

Dr. Bielekova

Yes, and, in fact, it is because these tools are not that ideal, right? So, in fact, by using the tools that are available, such as MRI or these cerebrospinal fluid markers that have been developed more than 40 years ago, the conclusion is that there isn’t inflammation in progressive MS, right, because all of them are basically decreased, with exception of IgG index which, as you said, remains stable for many, many years. So somebody who had, for example, infection during childhood can have elevated IgG index for the rest of their life.

So that was really the reason why we wanted to develop something that is more sensitive. And also, I think, the question really was, does cerebrospinal fluid reflect what’s happening in the brain tissue? And can we somehow develop technology that can tell us what is happening in the brain tissue without taking, of course, the biopsy, which is extremely invasive, and we cannot really use it in people, right? So how did you address that problem?

Dr. Komori

We developed a very good way to measure soluble biomarkers in the CSF with a new technique called Meso Scale Discovery.

Dr. Bielekova

So I think we should probably step back a little bit and say that our goal was to really look at the biomarkers that can point towards a specific cell, right? Because there are proteins that can be released by all immune cells, such as for example, chemokines, and, in fact, the vast majority of cytokines. But we were especially interested in looking at the proteins than can specifically point to one particular cell type, and so you did something else to really measure that, right? In fact, we all helped you to do that because it was so difficult, right? So we employed the whole lab to do the separation of cells. And then you were looking at which cells are producing these biomarkers.

Dr. Komori

Right.

Dr. Bielekova

So tell us about those three that really panned out as the best.

Dr. Komori

When we see the results of soluble CD27, soluble CD14, and soluble CD21, soluble CD27 correctly identified all inflammatory neurological disease and also only negative for noninflammatory neurological disease patients.

Dr. Bielekova

Whereas all of the traditional markers together, if we put all of them together, they could identify only about two-thirds of the patients. We were really surprised, because – I mean, the field believed, as Mika had said, right, based on the fact you no longer have contrast-enhancing lesions; the treatments no longer work; you don’t have clear cytosis, meaning a large number of white blood cells in the cerebrospinal fluid – the field and us, we believed that what we are going to see, once Mika unblinds these two cohorts of close to 200 patients each that we will see that progressive patients have significantly lower amount of inflammation. But that’s not what she saw. She saw something completely different and surprising. So what did you see?

Dr. Komori

Well we saw almost comparable level of intrathecal inflammation in both PPMS/SPMS to RRMS.

Dr. Bielekova

Not almost, right? There wasn’t any statistically significant difference.

Dr. Komori

No.

Dr. Bielekova

So on the group level, we saw the same level.

Dr. Komori

Absolutely. Yes, and it was so significant compared to a healthy donor and noninflammatory neurological diseases. So all healthy donor and neuro-inflammatory neurological diseases, they didn’t have high level of especially soluble CD27. But almost 90% of each MS subtypes had very high soluble CD27.

Dr. Bielekova

But when you did the ratios…

Dr. Komori

Then we did the ratio and calculated soluble CD27 per T cell in CSF. We found that even higher level of ratio results in progressive MS patients, both in primary progressive and secondary progressive. And for our MS patients the ratio is almost comparable to healthy donor and noninflammatory neurological diseases. That means, although we don’t see many immune cells in the CSF for progressive MS patients, those cells are in the CNS tissue. And it cannot move, but just shedding the soluble markers like soluble CD27 into the CSF. And we can detect that marker when we measure the CSF.

Dr. Bielekova

And I think it really nicely ties with the beautiful pathology studies that have been published that demonstrate that patients with progressive MS no longer have this very dense inflammation around the vessel, which is the type inflammation that is capable of opening blood-brain barrier, right? Which means that that’s the type of inflammation that is associated with contrast-enhancing lesions. But instead, when pathologists looked at normal-appearing white matter, they could see, you know, one T cell here, one T cell there, right? It’s really difficult to quantify it on the pathology level, because they never assay the whole brain. But your assay is, in fact, looking at the entire brain. And what your assay is saying is that the number of cells is basically the same in all of these different stages of MS disease process. What is really different is where they are located, right?

So, in relapsing/remitting MS, they are located in the perivascular aggregates, not much in the normal appearing white matter. That’s where they open the blood-brain barrier. But in the progressive MS they are located in the brain. And I think our conclusion was that, in fact, this may be the major reason why current treatments are not working for progressive MS, because basically we would expect that only those drugs can work in progressive MS that have very good penetrance into the brain tissue.

Now, I think that we also have to realize that just the presence of the cells in the tissue doesn’t tell us that they are pathogenic, right? So it may be that they are there, but something else is driving disability. But on the other hand, the data we have, for example, from recently announced ocrelizumab trial is really suggesting that these cells are indeed pathogenic, right? So I think that we can say that progressive MS is neurodegenerative disease only if we can eliminate inflammation from the brain of progressive MS patients, and it does not translate into stopping disability or significantly inhibiting disability.

But the data that we have published, and we are still collecting, are really suggesting that current treatments, in fact, do not eliminate cells from the brain of progressive MS patients, right? So I think the question of compartmentalized inflammation versus neurodegeneration in progressive MS is really open. And I mean my view is that probably both of them are going to be important, right? I think that just because there are immune cells in the CNS tissue, it doesn’t necessarily mean that neurodegeneration is also not present. But I think the hypothesis that progressive MS is no longer inflammatory disease, and it’s pure neurodegenerative disease – I think that hypothesis is, at the moment, not confirmed, right, because we don’t have the experiment where we would eliminate the inflammation.

MSDF

So both of you are physicians. Does this influence how you would treat people with progressive MS at all?

Dr. Komori

Yes, absolutely. So from now, when I see high ratio results of progressive MS patients – soluble CD27 per T cell – if they have high ratio, then I will not treat them with current immunomodulatory drugs. But may be a good idea to try more effective drugs to penetrate in the brain. But if the progressive MS patients, although they have high soluble CD27 but low ratio results, then it will be worthwhile to use some immunomodulatory drugs for them.

Dr. Bielekova

I would even kind of take a step back and say that in order to be able to use your tool for the treatment decision, I think we need to gain another type of knowledge which we don’t have yet and that is what are current treatments really doing on these type of assays and this type of pathology, right? So we really need to quantify each individual drug, how much it can affect intrathecal inflammation in patients with the open blood-brain barrier, where the drug actually can get into the tissue versus patients with closed blood-brain barrier, where potentially the penetrance is much, much, much more limited, right. I think that it brings back that case that I mentioned where, you know, we are using, for example, cyclophosphamide, and we are assuming that just because the drug is inhibiting immune response in the blood, it will inhibit immune response in the cerebrospinal fluid. And I think that those assumptions are just not tested, right? And, in fact, when we tested them, we realized that the effect on the intrathecal inflammation is extremely limited.

So I think that there is a knowledge that we need to gain, which is this knowledge of which MS drug is doing what. And, if we conclude that they are not doing a sufficient job, which I am afraid that’s going to be the conclusion, then we can use this technology to in fact develop new drugs, right? Because your technology is looking at the type of inflammation that cannot be measured by contrast-enhancing lesions. In fact cannot be measured by anything that we have available thus far, right? So how are we going to even try to develop new drugs for progressive MS?

Well, we can do it by doing large, Phase 3 trials like we have been doing thus far and looking at disability. But of course, that’s incredibly expensive, and it’s just very inefficient way to do it. So instead, doing small trials where you take patients because they have intrathecal inflammation, right. So you now measure; (A) how much inflammation; and (B) its compartmentalized inflammation. Then you can give them the drug, and then you say, ‘okay so now I’m going to measure’ – and you can do it in 3 months or 6 months, in much, much, much shorter time periods – and say, you know, ‘how much is this drug inhibiting intrathecal inflammation?’ And, in fact, that’s precisely what you have done in our RIVITALISE trial, right? Which, unfortunately, we stopped precisely because your assays determined that we are not achieving as much inhibition of inflammation as we were hoping to achieve. So I think that that makes drug development very efficient. And hopefully it will allow us as a society, to screen many, many more treatments on a yearly basis than what we can do currently.

Dr. Komori

I think if we can measure the cell-specific or pathophysiology-specific biomarkers, we can combine treatments.

Dr. Bielekova

Absolutely.

Dr. Komori

If, like interferon, it doesn’t work, let’s try natalizumab. If not, let’s try this, but if we know that interferon works for this side of the pathophysiology, but natalizumab works for this side of the pathophysiology, then we can combine them to more effective treatment.

Dr. Bielekova

Yes, and I think that I would say ‘more to come,’ right? So far Mika published data that relate to inflammation, but the lab is working very hard on biomarkers that reflect, for example, mitochondrial dysfunction, or neurodegenerative processes. And we absolutely believe that treatments will have to be combined, and that this, you know, basically assaying cerebrospinal fluid is going to be that tool that will, on one hand allow us to develop these new treatments, and on the other hand, allow us to treat patients smartly at the bedside.

[transition music]

MSDF

Thank you for listening to Episode Ninety-six of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. Msdiscovery.org is part of the nonprofit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is Vice President of Scientific Operations.

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

[outro music]

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

For Multiple Sclerosis Discovery, I'm Dan Keller.

[intro music]

Host – Dan Keller

Hello, and welcome to Episode Ninety-five of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller.

Today's interview features Dr. Michael Levy, associate professor of neurology at Johns Hopkins University. When we met in his office, he told me about his work on the role of T cells in neuromyelitis optica, or NMO. Finding antibodies to aquaporin-4 is indicative of NMO. But when Dr. Levy used aquaporin-4 reactive T cells, they could induce NMO in a mouse model, giving a clue to the role of T cells in the disease, and possibly opening up a new therapeutic avenue.

Interviewer – Dan Keller

What's different about this approach than what has been thought of previously?

Interviewee – Michael Levy

In neuromyelitis optica, there is the thought that the disease involves an antibody, the anti-aquaporin-4 antibody, that that antibody is involved in causing the disease. And what we demonstrated in this model is that we could recreate the disease simply by developing T cells against aquaporin-4. It's the exact same target as the antibody, but instead of using the antibody to exacerbate disease, we use T cells. And it works really well and causes optic neuritis and transverse myelitis, just like in the patient.

MSDF

Can you briefly describe your method?

Dr. Levy

We raised T cells in mice that don't have aquaporin-4. These mice see aquaporin-4 as a foreign antigen and mount an aggressive immune response against them, and we harvest those T cells from that animal. And what we do is we polarize them. We basically turn them into more aggressive types of immune cells in a dish. And then we transfer those T cells to a naïve mouse that does contain aquaporin-4. And those T cells attack the aquaporin-4, and it does so only in the optic nerves and the spinal cord and also a little bit in the brain.

MSDF

But aquaporin-4 is distributed more widely than that in the body.

Dr. Levy

That's correct. Actually, there's a higher level of aquaporin-4 in the lung, stomach, kidneys, muscle. Many tissues contain aquaporin-4, but the T cells decide which aquaporin-4 to attack. They are a thoughtful type of cell, and for whatever reason, and this is true in the human, too, the T cells only decide to go for those specific tissues.

MSDF

How does a mouse with aquaporin-4 get to an age where you can actually get these T cells out of it? What's the use of aquaporin-4 if they really can survive without it?

Dr. Levy

It's amazing that these knockout mice, they don't have any aquaporin-4, are completely viable. There are some abnormalities in function under certain stressful conditions, like stroke or brain trauma, but for the most part, they live normal lives. They must have a good compensatory mechanism that they don't need aquaporin-4, and that's fortunate for us because we can create these animal models.

MSDF

When you transferred these T cells to wild-type mice, what did you see?

Dr. Levy

Eight days after the transfer, the first thing we noticed is that the mice started blinking and the eyes became sunken into the head, and that's a sign of severe optic neuritis. And then two days later, they had a dragging tail. And a day after that, their hind limbs were paralyzed, and that indicated transverse myelitis.

MSDF

What's the role of the antibody if you can induce the disease with the T cell? And does the antibody in itself without T cells have an effect?

Dr. Levy

We looked at that, and what we found is that the antibody by itself has absolutely no effect. But in the context of a T cell attack, it can exacerbate the disease, and it does lend specificity to the pathology when you look at it under a microscope. If you add the antibody, there is more aquaporin-4 damage, and it recruits compliment, which causes that damage. So that's really the role of the antibody.

MSDF

Can you induce the antibody without T cells? Essentially is aquaporin-4 a T-dependent antigen?

Dr. Levy

We think it is, and that's based on the type of antibody it is. The antibody in a human is what's called an IgG1 subtype, which is a T cell-dependent subtype. And that bears out in the animal models as well.

MSDF

So the antibody is really an enhancer in the disease as opposed to an initiator?

Dr. Levy

That's our thinking. It's not just an enhancer, but also a biomarker of the disease. And maybe in some patients, the antibody is not as harmful, but more of just a biomarker.

MSDF

What's the significance of these findings, especially as it relates to human conditions?

Dr. Levy

We're always looking for a new target to treat NMO patients, and there were some who were thinking that we should be targeting the antibody to try to either remove it or soak it up somehow. And maybe our model suggests that we should be targeting the T cells. And if there were ways that we could retrain or reeducate those T cells not to attack aquaporin-4 and create a really specific therapy, then we could avoid these broader immunosuppressive therapies that are necessary now to treat these patients.

MSDF

Since you have a defined antigen in this case, and I assume you can make some of it, do you have any hope of being able to induce high-zone tolerance using it?

Dr. Levy

That is our goal, and we've partnered with a company now to try to create a vaccine therapy using that antigen target. Again, in the same way that a T cell is turned pathogenic with this antigen, we can then retrain that T cell to be tolerized to it. And so we're hoping to apply that sort of technology to humans.

MSDF

Now you're coming in at a late stage of the disease. I mean, someone has to present with the disease for you to want to treat it. So really, you can't prevent it. This would be a therapeutic vaccine, not a preventative vaccine?

Dr. Levy

Correct. A vaccine therapy more along the lines of retraining than preventing and preparing. Correct.

MSDF

Now this applies to NMO, but what about applying it to MS? With NMO, you've got a defined antigen.

Dr. Levy

That's exactly right. And with NMO, there isn't what we call antigen spreading, which is where the immune system decides instead of targeting that one antigen, it's going to spread. The epitope is going to spread to other areas of myelin and maybe other components of the central nervous system. With NMO, the antigen is really focused on aquaporin-4, and so that's our advantage. And in MS, there are a lot more targets, and it's probably more of a heterogeneous disease. It would be harder to develop a vaccine therapy for MS.

MSDF

Where do you go from here? What's next?

Dr. Levy

Next is demonstrating that the mouse model responds to a vaccine therapy approach. We'd like to show that the T cells can be stopped, even when they're pathogenically targeting the aquaporin-4. Transferred into a mouse, we need to demonstrate that a vaccine therapy can prevent their attacks.

MSDF

Have you looked or demonstrated T cell receptors specifically for aquaporin-4 fragments?

Dr. Levy

We're looking at that now. We're looking in human subjects. We isolate their T cells, and we're looking for a response to certain epitopes of aquaporin-4. That has been done by other groups, but we're looking for specifically pathogenic epitopes now.

MSDF

Is there any thought towards some sort of suicide experiment where these T cells that have become activated could then be killed because they're proliferating?

Dr. Levy

There is a company in Houston called Opexa Therapeutics. They're doing something similar to that. They're picking out patients' T cells that are reactive against aquaporin-4 and inducing apoptosis so that when these T cells are reintroduced to the body, there is a tolerization. So it is kind of the same thing that you're suggesting. And they are hoping to launch a trial like this by next year.

MSDF

Is there anything we've missed or important to add?

Dr. Levy

What I'd like to emphasize again is that by focusing on the T cells, we can really hone in on the very upstream early event and really specifically treat…I don't want to use the C word to say cure, but it's really focusing on the source of the problem, rather than treating all the downstream consequences, which is what we do now. So I think our approach has that specific advantage.

MSDF

An advantage over a more global nonspecific immunosuppression?

Dr. Levy

Exactly, which is what we're doing now.

MSDF

Very good. Thanks.

Dr. Levy

Thank you.

[transition music]

MSDF

Thank you for listening to Episode Ninety-five of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. Msdiscovery.org is part of the nonprofit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is Vice President of Scientific Operations.

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

[outro music]

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

For Multiple Sclerosis Discovery, I'm Dan Keller.

[intro music]

Host – Dan Keller

Hello, and welcome to Episode Ninety-four of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller.

Today's interview features Dr. Oscar Fernandez, a senior investigator at the Málaga Regional University Hospital in Málaga, Spain. When we met at a neurology conference in Chile, he reviewed for me some of the elements of risk stratification for second-line therapies for MS. That implies there are first-line therapies and probably third-line ones, as well – terms that Dr. Fernandez is not particularly fond of.

Interviewee – Oscar Fernandez

I am very much against that classification, but this is being used for clinicians, so I have to accept that. I believe that there is one drug for one patient, and I don't believe in lines. Because if you use lines, then you must be forced sometimes to do the passing through all these lines. And many times you must go indirectly from the very beginning to second or third line and the case is very severe. Anyhow, lines have been defined more or less just taking into account the benefit and the risk. And first line are those drug who are not terrible beneficial; they have more this efficacy, but they are very safe in the long term. This is the first line, and those are interferons, there are like four interferons so far, and glatiramer acetate, this is first line. And second line are those drug where are more efficacious but more risky also. So there you have natalizumab, fingolimod, alemtuzumab, and mitoxantrone.

And even you can go further for the third line, which is maybe bone marrow transplantation and some experimental therapies by now. There are many new drugs coming, and then we must try to classify these as first, second, or third lines. It's very difficult for clinicians today to image, for instance, ocrelizumab, which drug is that? Is it first, second, or third line? Is it very efficacious, is it very safe until now? So why it should be classified as second line? Probably the agencies will say this is for active relapsing or for active MS and just let the clinicians to use it properly.

Interviewer – Dan Keller

So what goes into the risk stratification? What parameters do you consider?

Dr. Fernandez

Yeah, the first thing is that most clinicians use a balance, for the balance of efficacy and safety. But then they put numbers. You must put numbers. I mean the numbers are there. I mean for low-risk drugs and for very mild diseases the number is 1 in 10,000. You can have severe adverse events 1 in 10,000. For moderate disease and moderate risk, a drug is 1 in 1,000; and for severe, this is risky drugs, is 1 in 100. Those are the numbers to put in the balance. And we know the numbers from the drugs, and we must tailor our decision based on that.

MSDF

Are the risks you're looking at purely progressive multifocal leukoencephalopathy, PML, or are there other risks you're considering in those numbers?

Dr. Fernandez

No, PML is just something that appear, but there are many other things to be taken into account. I mean all severe adverse events should be taken into account, and these are the numbers I have mentioned. MS is a very severe disease; it's a risky disease. So we can theorize independent of the severity of the disease and we must look for everything. I mean hematological alteration, hepatic alterations, opportunistic infections, and everything that can be produced by these drugs over these therapies.

MSDF

Is it only the drug or do you also take into consideration patient characteristics besides their MS; age, comorbidities, gender, lots of things?

Dr. Fernandez

Everything has to be put in the box; I mean all the things have to be consider. And it's not the same to use a drug in a patient which is also a hypothyroid, is diabetic or whatever. So comorbidity, age, sex, and everything has to be taken into account, particularly sex because many drugs can affect pregnancy issues. For instance, so we must take it all together and try to get the right decision.

MSDF

Is it a collaborative effort taking into account what the patient preference is either for disease risk, therapeutic risk, or other factors?

Dr. Fernandez

Yeah, I think there is to try to find out which is the best way. We know we has collaborate on that and there are a lot of people collaborating. For instance, in Spain, we have a network of MS, and we are doing tremendous advance publishing in this direction. And in Europe and in the world, I believe there is always networks trying to answer all of these questions. For instance, the latest one has been published more recently about the use of L-selectin to stratify the risk for PML in natalizumab users. And this has been very important collaborative study that has validated this measurement, L-selectin, as a factor to be taken into account to reduce the risk of natalizumab.

MSDF

Is this something new looking at biomarkers for risk?

Dr. Fernandez

Yeah, it's something new. It's still not implemented in most center. But we have been using that for the last two or three years. I have treated more than 250 and especially with natalizumab without a single PML case. Because we use everything at hand to try to reduce the risk of this severe complication.

MSDF

How long have those patients been on therapy, natalizumab?

Dr. Fernandez

Well, the longest one is 12 years already because this patient participated in clinical trials but they are still there. But all of them more than one year. And the majority of them more even than two years. But as soon as the risk gets over the figure that shouldn’t be got, these patients are withdrawn from the drug. And we have medical simulators now to use on different drugs. Although if you are able to keep the patients on this drug, the patients are perfectly well.

MSDF

Do you think the field is going to move more towards that than just looking at JC virus, which is very prevalent anyway?

Dr. Fernandez

No, I don't think we should necessarily look for JC virus in every patient. We must look for other things like, for instance, the cases of PML that appear with dimethyl fumarate. I mean there are two cases, as far as I know, but we must look for lymphocytes. I mean doctors always took care of toxicity degrees one, two, three, and four, and we know what to do with these toxicity degrees. And this has not been well done probably in the last years for some clinicians, so we are assisting to some complications because we don't follow the rules strictly. We must follow the rules. Lymphopenia shouldn't be maintained for long periods. Because lymphopenia can be associated with infections, can be associated with tumors. So we better control for these factors. So let's look everything.

MSDF

Do databases like MSBase add to the knowledge or information?

Dr. Fernandez

Yes, databases probably are fundamental. I mean there are many databases already around the world, and the possibility to share data and to have immediately data from many, many patients is helping us to tailor decisions.

MSDF

Have we missed anything important, or is there anything interesting to add?

Dr. Fernandez

Yes, I think still there is a tremendous variability between neurologists. And there must be some kind of educational effort in the next future to try to reduce variability. Because by now, there are many drugs; we have confusion. Neurologists treat patients very differently in different countries, even into the same country, into the same hospital. So we must still make a tremendous effort maybe through databases or through evidence-based medicine and try to reduce the variability of what we are doing for our patients.

MSDF

Excellent. I appreciate it. Thank you.

Dr. Fernandez

Okay, thanks to you.

[transition music]

MSDF

Thank you for listening to Episode Ninety-four of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. Msdiscovery.org is part of the nonprofit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is Vice President of Scientific Operations.

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

[outro music]

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

For Multiple Sclerosis Discovery, I'm Dan Keller.

[intro music]

Host — Dan Keller

Hello, and welcome to Episode Ninety-three of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller.

Today's interview features Dr. Lilyana Amezcua, an assistant professor of neurology at the University of Southern California in Los Angeles. Part of her work focuses on defining racial disparities in MS, particularly among the Hispanic community. When we met, she said the prevalence of MS among Hispanics in Latin America has been increasing over the past 20 years, and their clinical characteristics are different from those of whites. As Hispanic Americans constitute one of the largest minorities in the U.S. population, she looked into their clinical picture, as well.

Interviewee – Lilyana Amezcua

And so we initially did a first observation in 2011 noting when we examined close to 200 MS patients of Hispanic background self-identified that they were at twice the risk of presenting with optic neuritis and spinal cord problems compared to whites. There is some literature indicating throughout Latin America that these observations could be related to an Asian background. And so when we think about a Hispanic, we think about an umbrella that is related to an intermixing of European, African, and Asian derived background or Native American. So that diversity along with the cultural diversity could have some implications in the way that MS behaves and including risk. And that is one of the theories going around that that's why they don't get MS that much because of an Asian background. However, again, like I mentioned, in the last 20 years more cases have been reported.

Interviewer – Dan Keller

Haven't Asians been reported to have this opticospinal sort of MS? So would that feed into this optic neuritis finding with the Hispanics?

Dr. Amezcua

That is correct, and actually a second study of ours that we did several years ago was to actually specifically look for that definition of opticospinal MS. And so what we found within 200 or so patients was that indeed when we applied that definition, very few met that criteria. But irrespective of that, and we made sure that every case was negative for aquaporin 4, which is an antibody that you commonly find in more of the NMO spectrum disorders, that these individuals did not have this aquaporin 4, but yet close to 20% looked like they had spinal cord lesions that could be associated with opticospinal.

So that observation, of course, led us to think, well, okay, we should look further. If we do think that Asian ancestry could be important, would some of those clinical characteristics be associated with that type of global ancestry? And in fact today we have a poster related to taking the population that we just presented and looking at their genetic variants, which are mostly noting that the European genetic variants are also found in the Hispanic, but now going forward and looking at, well, what about global ancestry and their clinical characteristics? And in that poster, that abstract, we find that the higher proportion of Asian background you have, the higher risk of presenting with let's say, an optic neuritis. Now that doesn't necessarily say that this is just specific for optic neuritis, but it could going forward let us know about the mechanism behind optic neuritis, which is also found in MS, also found in NMO, and these optical spinal forms of MS.

MSDF

How did you go about looking at the genetics of the population?

Dr. Amezcua

Going about the genetics actually went back to the fact that when I would say, I'm studying Hispanics, people would ask, what is a Hispanic? And it is true…Hispanic…and so it is defined, you know, when you define it it's well, you can be from Cuba, you can be from Mexico, you can be from the US. But really what links us is…and I say linked us because I'm one of them…is the fact that there is a genetic background that is shared. And there's also cultural aspects that are shared. The cultural aspect is probably going to be important when we start examining the environmental aspects of MS.

MSDF

What did you find?

Dr. Amezcua

We just started basically with vitamin D. We looked at vitamin D levels in Hispanics with MS compared to whites with MS, and we found that significantly lower levels were among the Hispanics. This is not surprising. This is expected, actually, because of the skin coloration and sun exposure probably differences, but it's also widely known that Hispanics would have lower vitamin D levels. Of course, that doesn't answer, well, if they have lower vitamin D levels, if their risk of MS is less, it doesn't give us any explanation. But we know that their vitamin D levels are low.

Other aspects that we have looked at is just examining differences by migration. So we know in MS that migration, usually, depending on when you move from one place to the other and looking at the risk of MS in the underlying country, that will be modified depending on the age of migration. And so of course Hispanics in the US, again, along with their diversity, they're diverse in the fact that there are many that are US born and there are many that are immigrants. So we looked at differences by this, and we found tremendous amount of differences. One was that the US born appears to have an increased risk of developing MS at a younger age. And this again is just validating some of that information that we know about MS in the past, right, coming from a lower prevalent region and being born in a place of higher risk.

But the second was that, which we were surprised, was that the immigrant, despite being here, let's say 25 years, they developed MS after they had emigrated from their country, on average, 15 years later. So that's interesting. That's again calling for us to investigate, what environmental encounters might have they had when coming to this country? And the third was that respective of this, of, you know, disease duration, there was an independent risk factor for the immigrant to develop ambulatory disability at a shorter time. So that's telling us that, again, well, one is differential environmental exposures. But could the immigrant and the US-born also just be two different populations in terms of, again, what does Hispanic mean? That's where we are.

MSDF

In that sense, could you correlate vitamin D levels or anything else with the amount of European background or indigenous Central and South American background they had?

Dr. Amezcua

I think that's an excellent idea. You know, I think that could be done, to look at the US-born versus the immigrant. Now there is a large study conducted by Dr. Langer-Gould that's examining the risk of MS within Hispanics, whites, and African Americans in relationship to vitamin D and their HLA. So that will give us information on vitamin D. But absolutely we know that within Hispanics, we're going to have to separate groups because it's just such a big umbrella.

MSDF

It's also a big umbrella in terms of cultural background. It's not uniform culture whether you're from the Caribbean or Mexico or born in the US.

Dr. Amezcua

Absolutely. So culturally we're going to have to tease that out. And it's simply starts by learning about, well, what are those cultural differences? Which could be from simple perceptions and their access and utilization of care, which needs to be first addressed, or to go forward and then say, well, let's see if there's biological differences. First, I think, you know, between the US-born and the immigrant, the differences could be explained also by sociocultural factors. And those need to be teased out. And then from there look to see, well, is this really a health disparity? Or is it an inherent biological difference of the disease, which we also expect to find.

MSDF

Do you think that the results you find in this population is going to be more generalizable or relatable and give you some clues into what's going on with anyone who is getting MS or not?

Dr. Amezcua

Absolutely. That is the goal. While that diversity is complex, it's also a positive aspect because it will allow you to tease out a lot of those factors. And so within the admixture, of the genetic admixture, one can say, well, you have less European background. But what about that Asian component that is not found in your general European? It doesn't mean that it's not going to be found. Instead of looking for, I guess, a needle in a haystack, you will just be looking it in a block and maybe find something new or lead us to understanding of mechanisms, again, from the optic neuritis and the global ancestry. We are hoping that this is beyond just understanding one population, but understanding MS, which is the target population.

MSDF

Have we missed anything important?

Dr. Amezcua

There is definitely a lot to do, and I think it's an effort that cannot be done alone. And so combining it with different centers that have the same interests and population is what the goal is, is to create a network of centers that are interested in defining this population, to move faster.

MSDF

Great. Thank you.

Dr. Amezcua

Great. Thank you.

[transition music]

MSDF

Thank you for listening to Episode Ninety-three of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. Msdiscovery.org is part of the nonprofit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is Vice President of Scientific Operations.

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

[outro music]

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

For Multiple Sclerosis Discovery, I'm Dan Keller.

[intro music]

Host – Dan Keller

Hello, and welcome to Episode Ninety-two of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller.

Today's interview features a conversation with Dr. Shiv Saidha, an associate professor of neurology in the Division of Neuroimmunology and Neuro-infectious Diseases at Johns Hopkins University in Baltimore, Maryland. His work has focused on the retina in MS, using the technique of optical coherence tomography, or OCT, to follow the disease, assess and monitor therapeutic strategies, and to better understand the pathobiology of MS. I asked him why the retina is of interest in MS and about the utility of OCT.

Interviewee – Shiv Saidha

OCT is the optical analogue of ultrasound B mode imaging. And it's a noninvasive technique that has a lot of utility in quantifying the ultrastructure of various tissues, including the retina. We have a lot of interest in being able to quantify retinal structures specifically in multiple sclerosis because optic nerve pathology, which basically refers to affliction of the optic nerve as part of the MS disease process, is virtually ubiquitous. At the time of postmortem examination of MS patients, 94 to 99% of MS patients are found to have demyelinating plaques within their optic nerves.

So the premise is that demyelination within the optic nerve results in retrograde degeneration of the constituent fibers or axons within the optic nerve. And since those axons or fibers are derived from the retinal nerve fiber layer, which is the innermost layer of the retina, this layer is felt to thin out as part of the MS disease process. Additionally, the neurons – referred to as ganglion cell neurons located in the ganglion cell layer immediately below the retinal nerve fiber layer from which retinal nerve fiber layer axons are derived – are also thought to drop out as part of the MS disease process.

We traditionally conceptualize optic nerve pathology in MS as being an acute phenomenon, namely acute optic neuritis, which does occur in up to, you know, 20 to 70% of MS patients; and in 20 to 25% of cases of MS is the initial hallmark clinical manifestation of the disease process. But beyond acute optic neuritis, there is subclinical optic nerve pathology, which we refer to as subclinical optic neuropathy ongoing within the optic nerves of MS patients.

And so, if we had a technique or an ability to accurately quantify the effects of optic nerve pathology or optic neuropathy – in other words, if we had a way to quantify retinal nerve fiber layer thickness and thickness of ganglion cell…the layer within which ganglion cell neurons are located in the retina – that would provide a substrate or insight into the state or integrity of the optic nerve. And so, optical coherence tomography is a technique which allows us to do this. It allows us to measure thickness of the retinal nerve fiber layer not just around the optic disk which we refer to as the peripapillary retinal nerve fiber layer but also in the macular region.

And with the advent of novel segmentation techniques in OCT – many of which are now commercially available – we now are also afforded the capability of quantifying thickness of other discrete retinal layers such as the combined thickness of the ganglion cell layer and inner plexiform layer, which many of us refer to as GCIP or some also refer to it as GCIPL. Conventionally, peripapillary retinal nerve fiber layer thickness – at least in cross-sectional studies – was found to be associated with high and low contrast visual function, as might be expected since the retina subserves vision as a function.

But interestingly, early studies even found that thickness of the peripapillary retinal nerve fiber layer was associated with disability scores as determined by Expanded Disability Status Scale scores or EDSS scores in MS patients, as well as whole brain volume in MS patients, implying that these metrics derived from OCT somehow provide a window or insight into the global MS disease process. With time, we started to realize that the GCIP thickness might actually be an even more powerful measure of the state of integrity of the optic nerve.

GCIP thickness seems to be more reproducible than that of the retinal nerve fiber layer. It has a intraclass correlation coefficient of about 0.99 with a very tight confidence interval. It has superior structure function correlations with EDSS scores, brain volumes, as well as high and low contrast visual function, as compared to retinal nerve fiber layer thickness. This is really a very interesting and important point about, you know, the potential utility of OCT. Because with this thickness of the GCIP, what we were really getting is a very good estimate of neuronal integrity.

And, one of the factors that has been limited in terms of MRI – or magnetic resonance imaging – is the ability to really accurately and reproducibly quantify collections of axons and neurons. Now in terms of MRI, we often think that the white matter is a very good reflection of axonal integrity, and that gray matter is a good reflection of neuronal integrity. This is not necessarily the case, however. In terms of the white matter, quite a lot of inflammation obviously occurs within the white matter in MS brains. And when that inflammation occurs, white matter volume increases. And then, as that inflammation subsides, the white matter volume drops.

And then, as the next wave of inflammation comes in, again, there's swelling and the white matter volume goes up. And as it resolves, the white matter volume comes down. And so there's this waxing and waning in terms of white matter volume which limits the utility of white matter volume. And in fact, it's for that particular reason that many researchers have found that when you track MS patients over time that the bulk of change is actually seen within the gray matter.

In terms of the gray matter, there is a lot of axons present within the gray matter. And so, gray matter volume is not just a pure measure of neuronal integrity. And the other thing is that the axons within the gray matter are predominantly myelinated similar to within the white matter. And so these brain substructure volumetrics are confounded by myelin too. The retina is an unmyelinated central nervous system structure. And so the measurements that we derive with OCT are not confounded by myelin. And secondly, GCIP thickness does not seem to increase during inflammation of the optic nerve.

There's been a number of studies showing that during acute optic neuritis peripapillary retinal nerve fiber layer thickness increases. There's a number of reasons for that: there's inflammation within the optic nerve, and so there's edema. And so we think that some of that edema may track down to the retinal nerve fiber layer. And there may also be some impaired axonal transport resulting in congested axons within the retinal nerve fiber layer. In addition to that, the retinal nerve fiber layer also contains the bulk of glial cells. And by that, I was mainly referring to astroglia. Now microglia are thought to be present throughout the retina, but there's really no astroglial confound of GCIP thickness as well.

During acute inflammation in the optic nerve, GCIP thickness was not found to increase. And so if you take a patient, as an example, with an acute optic neuritis now, and then you repeat the OCT scan six months later, the GCIP thickness at six months subtracted from that at baseline is felt to be a fairly accurate reflection of net neurodegeneration in terms of net loss of ganglion cell neurons. That absence of edematous or inflammatory or swelling related confound of GCIP thickness yields yet another advantage for this particular measure.

Interviewer – Dan Keller

How does the time course of changes in the GCIP correlate with brain MRI? Can it be predictive or are they in lockstep or how do they relate?

Dr. Saidha

Yeah, so that's a great question. I think one of the things with OCT research has been that the bulk of research to date has been cross-sectional. And so it has really been one of those key things on our mind is does the way that the GCIP atrophies or thins really mirror what's happening in the brain? In other words, are they locked in together? Are the rates of GCIP atrophy and brain atrophy actually associated with one another, or are they a little disconnected?

So in a recent study, which we published in Annals in Neurology, we tracked a little over 100 MS patients for roughly a four-year period, and we did annual MRI scans with a 3-Tesla scanner, and we did six monthly OCT scans. And very importantly and interestingly, we found that the rate of GCIP atrophy was highly correlated with the rate of brain atrophy and a particular rate of gray matter atrophy. Of course, that's a little bit to be expected partly on the basis of what I said earlier that white matter atrophy in itself is not as well detected as gray matter atrophy.

And then when you look by subtypes of MS – meaning, you know, relapsing MS versus progressive MS – we found that the rate of atrophy was even better or more highly correlated in terms of its association with brain atrophy rate. In fact, it appeared that the rate of retinal atrophy could predict 80% of variance in rate of brain atrophy, which is fascinating because it really does imply that what we're seeing within the retina of MS patients is a reflection of global central nervous system pathology.

And the pathobiological changes that we can detect and monitor with OCT appear to very nicely reflect what's happening within the brain. And that this cheap, noninvasive, easily tolerated, easily repeatable technique that's painless can provide so much insight into this disease process is really quite fascinating and really phenomenal when you consider the increasing and growing need for an ability to measure and monitor neurodegeneration in this disease process. We traditionally conceptualize MS as being an inflammatory demyelinating disorder of the central nervous system, and absolutely there's inflammation that occurs as part of the disease process. And when acute inflammation occurs, there's some immediate damage to axons on the form of axonal transection. And then when axons do not have enough myelin around them or are devoid of myelin over sustained periods of time, that normal protective environment for axons is not present, and so we feel that those axons slowly neurodegenerate.

The advent of putatively neuroprotective and putatively remyelinating therapies now more than ever increases our need for an ability to be able to track neurodegeneration. And in fact, it is neurodegeneration that is the principal substrate of disability in MS. And while the inflammation may be at the root cause of this neurodegeneration, the disability that patients have is better associated with the amount of neurodegeneration that's present. So, it's possible – and we postulate – that OCT could be a very useful outcome measure in terms of assessing therapies which are putatively neuroprotective and/or even neurorestorative or remyelinating.

MSDF

Do you think that there is a common process going on more centrally and in the retina causing the changes in both? Or is it possible that there is more central degeneration, which then is transmitted peripherally causing problems in the retina?

Dr. Saidha

So that's a great question. We think that the bulk of the retinal changes that we're observing are related to pathology within the optic nerve. And because optic nerve pathology is basically ubiquitous as part of the disease process, we think that the changes that we're seeing within the retina are really just a reflection of what's happening throughout the central nervous system.

Now, you do raise a very important point though. Although we think that the bulk of the change that we're seeing within the retina is related to pathology within the optic nerves, that does not exclude the possibility that some of the changes that we're seeing – in terms of thinning of the retinal nerve fiber layer and GCIP, in particular – are actually related to transsynaptic degeneration. Meaning that if you have a distant lesion or distant pathology that as an axon dies that the next neuron and axon, as part of a sequential chain, is not affected. And that's something that we're actively studying at the moment to try to better understand the effects of transsynaptic degeneration on retinal measures. There is some data to suggest that there is transsynaptic effects on retinal measures, but my own view is that longitudinal studies to definitively establish this are currently lacking.

MSDF

Do you have to watch out for a history of optic neuritis when you look at the OCTs? Does that affect what you're finding?

Dr. Saidha

I think it does. So, if we are kind of going to say that what we're seeing in the retina is a general reflection of what's happening in the brain, we have to at least consider the possibility that a severe inflammatory event with disproportionate local retinal tissue injury might have an affect on the global relationships between OCT derived measures and brain measures. So, when we look at the relationships between rates of GCIP atrophy and rates of brain atrophy, we find that in eyes with a history of optic neuritis that that relationship is not as strong. And we think that that may be the case because immediately following optic neuritis there's an excessive amount of local tissue injury. And that local tissue injury that results in excessive loss of retinal nerve fiber layer and GCIP tissue somehow masks the global information that we're deriving from OCT.

But then what's interesting is that although a history of optic neuritis seems to be relevant at least in the relapsing-remitting subtype it seems to be less relevant in secondary progressive MS. Part of our hypothesis for this – although it needs to be better elucidated and studied – is that brain atrophy continues on following the optic neuritis, and let's just say it carries on, as an example, at the same rate that it did beforehand. Well eventually, the rate of retinal atrophy, although there was initial disproportionate surge in neurodegeneration within the retina, there will be some ongoing neurodegeneration occurring too. And eventually the two rates will become realigned again in the future.

Kind of to get at that point we also looked at rather than just history of optic neuritis we looked at whether baseline GCIP thickness might have an impact on rate of GCIP atrophy to kind of expand a little bit upon that hypothesis. And indeed, what we found was that rate of GCIP thickness at baseline is highly associated with rate of GCIP atrophy. In kind of simplistic terms the way I conceptualize this is that the more retinal tissue that's available the faster the potential rate of retinal atrophy is. And if there's less retinal tissue available, then there's maybe less potential for that rate to be as fast. If the rate was to remain steady the entire time from the day that the disease first begins – and I think this also applies to the brain too – it wouldn't be very long before there's no tissue left.

MSDF

You had alluded to looking at new potential therapies using OCT as an outcome. Does that also mean that it may have utility in looking at current disease-modifying therapies and being able to compare them?

Dr. Saidha

So that's an excellent question. In fact, that's actually currently no data available that I'm aware of that has assessed the effect of currently available disease-modifying therapies on rates of GCIP or retinal nerve fiber layer thickness atrophy. And I think that's something that a lot of academics and people who do research utilizing the visual system and a particular OCT would be interested in seeing. We have such data – and such data is routinely collected in terms of effects of disease-modifying therapies – on brain volume, and this is something that's now fairly standard to be collected as part of clinical trials. It may be useful to know whether currently available disease-modifying therapies have differential effects on rates of retinal atrophy. Which would imply that maybe in addition to having a role as an outcome measure in trials of putative neuroprotectants, as well as neurorestorative agents, that maybe OCT might actually also have a role in studies of potentially anti-inflammatory treatments or treatments which modulate or suppress the immune system, as do most currently available licensed disease-modifying therapies.

MSDF

Very good. I appreciate it.

Dr. Saidha

Thank you very much.

[transition music]

MSDF

Thank you for listening to Episode Ninety-two of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. Msdiscovery.org is part of the nonprofit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is Vice President of Scientific Operations.

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

[outro music]

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org. For Multiple Sclerosis Discovery, I'm Dan Keller.

[intro music]

Host – Dan Keller

Hello, and welcome to Episode Ninety-one of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller.

Today's interview features Dr. Jorge Nogales-Gaete, who is Chief of the Department of Neurology and Neurosurgery in the Faculty of Medicine at the University of Chile in Santiago. We spoke at a neurology conference in Santiago about MS patients' perceptions of their clinical care and the importance of the healthcare team's understanding those perceptions.

Interviewer – Dan Keller

Let me ask you about the ethical and clinical imperatives for the healthcare team when they encounter an MS patient to learn their perceptions, to learn their desires, their approach to therapy.

Interviewee – Jorge Nogales-Gaete

I think the patient has at least two different condition on other disease, chronical disease. The first is the age. They're too young to have a chronical disease. There's nobody is prepared to have one. You have think about your lives, your project of life, and then you have a strong situation that is the diagnosis. Then, this is unexpected. It's a disruption. It's not natural. When you are old and you have blood hypertension, well you have time to right it. But when you are so young and you have this kind of disease, it's very strong.

And the other situation is that this disease is not usually the same all the time. You have period that you are normal, you have no manifestation, even the diseases on you. And other you have problem. And in each situations, you are thinking very different. Then you must consider in relation with the patient that nothing is stable. In the consideration of the disease, then you must go again to talk about doubt, about risk again and again. And this is different to other chronical disease.

MSDF

There's so many variables: there's the patient, the nature of the illness, the nature of the clinician. But also, within the patient is education, knowledge, understanding, age, gender, family, economics. How do you make sense of it all?

Dr. Nogales-Gaete

Well I think that the first situation is fear. All patients have fear; it's something new. They have doubts, and this is common. You have more prepare in your cognitive system to aware about this. But the fear is just for all equal. If you are warned, if you listen, what they want to know is more easy. Right situation for each patient, each patient is different. Then you must make the effort to be different for your each patient that you have in this moment.

MSDF

Each patient is different from the other patient, but each patient is different over time from what he was before.

Dr. Nogales-Gaete

Yes, this is the situation. Then, you must be prepared to take the situation again and again and again and be prepared. I never said we're talking about this. When we talk, we add in another situation, I have another fear, I have another sensation, I have not this problem that now is my problem I want to talk that again.

MSDF

When you first see these patients, when they're first diagnosed, do you lay out an entire treatment plan? How do you prepare them for the varying course of the disease?

Dr. Nogales-Gaete

I try to never give all the information in one meeting. I prepare the patient. I said well we are searching something, we find something, but we need to see again. Even when you have a second opinion demanded, I just take my time to say well this is the first situation. You are in this, but not to say all the things. Not to say well this is the disease, you need this treatment, this is the situation. No. You’re having a chronical problem, it seems to be autoimmunity, it seems to be of the central nervous system. Probably it's MS, and we need to work it. Then I prepare first the patient, the family, and then arrive to the diagnosis. And what's meaning in term of care, treatment.

MSDF

Do you try not to make predictions because if you're wrong the patient may lose trust, may have even more doubt?

Dr. Nogales-Gaete

Yes. It's not possible to make prediction; that's the first thing. Then, if you make prediction, probably you are wrong. When you are able to make prediction, it has some value because to make a good prediction you need at least 10 years. And it has in sense a prediction 10 years later. I think well, the general population goes in that way, but it hasn’t sense for you specifically.

MSDF

So it sounds like all you can predict is the unpredictability of the disease.

Dr. Nogales-Gaete

Yes. And this is important. This is important because you have the possibility to think in a bad scenario but also in a good one.

MSDF

Do patients want frequent contact and updates or does it vary by who you're talking to?

Dr. Nogales-Gaete

General, at the beginning, the patient need more contact or when the disease goes worse. But in general, no. When they are in good condition, they need to live the good time without a physician or a medical care team.

MSDF

What about patients talking to patients or support groups?

Dr. Nogales-Gaete

Well, this is a difficult situation. Because you have a vast selection of the person who are very good; they don't want to go to see the person who had in bad condition. Then the selection is person in bad condition. And this not reinforce the spirit. It's a political good situation to represent needs. But to work the spirit it's not a good solution.

MSDF

What about learning coping techniques when they have an exacerbation or even emotional coping techniques because of the doubt and unpredictability?

Dr. Nogales-Gaete

In this situation, probably it's important the background of the patient: the culture, the individual level. It's more easily the person who have a better condition – educational and economical condition – to adopt methodologies of coping.

MSDF

How is it, as a physician, being in a specialty that has such wide-ranging disease type and unpredictability of disease course in the patients? I mean some medical specialties the orthopedist says that's a bad hip; I'm going to replace it. You're in sort of the area that we might say is like nailing Jell-O to the wall; it's very hard to nail it down.

Dr. Nogales-Gaete

I think that MS give you the opportunity to think about the real reality. All are vulnerable, all of us. Then people with MS has this more clear. But just more clear, we are talking now, but nobody know about tomorrow. Then life is uncertainty. Then you must to admit that you don't have the control. You have the possibility to moderate something, but then you don't have the control.

MSDF

What about approaching general health concerns? Do people look to the neurologist as their general practitioner, or do you have to reinforce with them, yes you have to watch out for your cholesterol and everything else, you need to see someone else also?

Dr. Nogales-Gaete

We have a public organization based on family physicians general practice. And then you have to be sended to a specialist. And the specialists in general are more aware about the proper field. Then it's a little bit separate, each problem. It's not a good situation. But, cardiologists give the cardiology solution; neurologists make theirs. We have probably internal medicine is the more complete possibility to see all the patient in a comprehensive way.

MSDF

I guess the real question is, do you have to encourage them to also remember they have general health needs too, and those should be addressed by the generalist.

Dr. Nogales-Gaete

Yes. You have a problem, but you have the possibility to won two lotteries. Then, you need to attend it. If you are in a good health situation, it's better for all. Then try to be in a good situation about your cholesterol and other things: blood pressure, don't smoke.

MSDF

Have we missed anything that's important to address?

Dr. Nogales-Gaete

I think that we are in the hope era. Twenty years ago we have no the same tool that we have now. We have another drugs, we have another meaning of the disease; we understand more the patient necessities. Then it's mean more than a single drug that modify the disease. Patient have fatigue, has fear, has doubt, have pain, have depression. And you need to understand all of these things. Because if you make the correct diagnosis and give the drug that modify the illness, nothing happen with the everyday life of the patient. The everyday life need another answer. That mean it's not just a neurologist, it's not just the physician. You need all the health team that work in this patient.

MSDF

I appreciate it. Thank you.

Dr. Nogales-Gaete

Thank you.

[transition music]

MSDF

Thank you for listening to Episode Ninety-one of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. Msdiscovery.org is part of the nonprofit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is Vice President of Scientific Operations.

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

[outro music]

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

For Multiple Sclerosis Discovery, I'm Dan Keller.

[intro music]

Host – Dan Keller

Hello, and welcome to Episode Ninety of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller.

Welcome to the weird world of the U.S. pharmaceutical market. A few outrageous cases of drug price gouging have made the headlines, but in multiple sclerosis, a more serious concern is the steady annual rise in cost of all disease-modifying therapies, or DMTs. So says Dr. Daniel Hartung, a researcher at the Oregon State University/Oregon Health and Science University College of Pharmacy. In a recent study, he found that MS drug prices over time outpaced both inflation and similar biologics. It’s not just the new drugs. As each more expensive DMT comes to market, the prices of older drugs also race to catch up. It’s affecting the drugs available to patients and causing other concerns.

Interviewer – Carol Morton

Can you tell me what questions you were asking and why?

Interviewee – Daniel Hartung

Sure. So the study that we did had its origin after having some conversations with some neurologists at OHSU about increasing frequency of seeing their patients facing larger and larger, not only cost sharing and copays from the insurance companies for drugs for MS, but also increasing restrictions, typically from insurance companies in kind of what medications they were supposed to take first prior to perhaps failing one, then going to another medication for MS. And so this is all kind of happening in the context of what they were seeing as just higher prices for some of these medications.

And so what we decided to do is…no one's really done this…is look at in a systematic way the trajectory of pricing for MS drugs, essentially since their approval until we went through the end of 2013. And to look at what the just general trend was, try to figure out if there were certain specific factors that were associated with higher prices over time, like the approval of newer agents, things like that. That was kind of the general objective of the study.

MSDF

And then how did you go about conducting this study? Is it hard to find that data?

Dr. Hartung

It can be. So I'm fortunate to have access to some data set that has longitudinal pricing data for pharmaceuticals for the past 30 years or so. And so from my perspective, it wasn't difficult. But essentially we used this data set that collected average wholesale price, as well as wholesale acquisition cost, so kind of the two usual, most common (I'll call them) sticker prices for drugs. And so this data set for all medications, it kind of tracked pricing of medications over time. And so that was the core data set for our analysis.

MSDF

And so you pulled the multiple sclerosis disease-modifying therapies out of that. How many did you look at?

Dr. Hartung

So in our study we looked at 11 medications for MS. They included the three what are typically called platform therapies that have been on the market for about 20 years now. Those include Avonex, Copaxone, and Betaseron, and just followed them through time, through the approval of several other new agents, like Tysabri. And then there's in the last five to six or seven years, the FDA has approved several agents that can be taken orally, Gilenya, Aubagio, and Tecfidera now. And there was a couple other kind of miscellaneous agents that were kind of variants of the interferons and things like that.

MSDF

And then what did you find?

Dr. Hartung

Well, there are several interesting things, but I think one of the most striking things is that the prices for the platform therapies, Avonex, Betaseron, and Copaxone, were pretty stable for at least 10 years from their approval in early to mid-90s. And then, essentially what we observed is that new agents that came on the market, starting with Rebif in about 2001, came out, and they were usually priced about 20% to 30% higher than the existing therapies. And what we observed is that when these new agents came out or approved, that these higher prices, the cost or the price of kind of the platform therapies quickly escalated to almost match the price of the newer agents that were approved. And this pattern kind of repeated itself and actually became more intense when the newer oral agents came on the market in the last five or six years.

So the cumulative effect of that is in the early 2000s, Copaxone, Betaseron, and Avonex were priced about $10,000 to $15,000 a year. And at the end of our study, all of the agents that are currently approved were priced between $50,000 and $60,000 per year. And so we tried to quantify kind of the rate of increase and compare that with other kind of benchmarks: inflation, prescription drug inflation. What we found is that the price increase for those agents was well above what you'd expect for not only just general inflation, but also prescription drug inflation.

MSDF

MS drugs, the cost of all of them, not just the new ones, are increasing at a rate higher than any other drug category?

Dr. Hartung

In addition to looking at kind of standard metrics of inflation, we compared the price increases for the platform therapies to what we considered kind of comparable biologics. So we looked at a class of medications called tumor necrosis factor inhibitors, which are used for immunologic conditions like rheumatoid arthritis. And what we found is that the price increases for the platform therapies for MS increased substantially and significantly above price increases for those medications for the tumor necrosis factor inhibitor. So from our study, from our perspective, prices increased higher than they did for these TNF inhibitors.

We haven't really compared them across other classes of drugs, but there are some new publications that have looked at price increases for other agents, such as in other classes like insulin, drugs for diabetes, and cancer agents as well. The numbers are slightly different, but the trajectories look pretty similar. So in the last, you know, 10 years, there's been almost it seems like a logarithmic increase in the price of many of these agents and classes.

MSDF

So is this a case of a system that has incentives that maybe aren't as well matched to patient needs as they should? What's going on here?

Dr. Hartung

I mean, that's a good question. Definitely there's a system. The market-based system for pharmaceuticals in the United States is incredibly dysfunctional in that it's very dissimilar from any other kind of consumer market for technology, phones, cars, things like that, where you typically see prices go down after a while. And you don't see that in health care or in drugs. You see just prices increase. And so there's a dysfunction that just kind of is core to the economics of health care.

And then I think there is an element of pharmaceutical industries pricing these agents essentially what the market will bear. Now my opinion is that a lot of the aggressive increases in price were initially seen with some of the cancer agents. And so I think that in that field there is a kind of pushing of the envelope for many anti-cancer drugs that's now has proliferated to other classes of drugs, including MS agents.

The other element that's kind of unclear and adds to the murkiness to this is that, you know, our study and other studies that have looked at what I'm calling pricing of the agents use average wholesale or WAC and with some sort of adjustments for rebates or discounts. So typically third party payers or pharmaceutical benefits managers will negotiate with pharmaceutical industry to lower the cost of the agent for the payer. But all that information is typically proprietary, and so it's really difficult to know what the actual cost of the medication is, unless you're paying cash. If you're paying cash, then the cost is going to be pretty close to the price that's set. So people who don't have insurance are paying the most, and the people with insurance, Medicaid, any sort of governmental insurance, they're paying typically AWP minus a certain proportion or WAC plus a proportion percentage essentially based on the rebate that they get.

So that adds a little bit of kind of uncertainty. Pharmaceutical industry may come back to say that, you know, we're giving pretty good discounts on certain medications in certain payers, but from the data we have and the pricing data, there's just been this aggressive increasing in prices. And we don't know if it's being mitigated by increasing rebates and discounts over time. So it's complicated.

MSDF

What do you hope people will do with this information? It does sound like a complicated system that's almost unapproachable for the individual patient or individual doctor. What can people start doing now? Where does the responsibility or responsibilities lie?

Dr. Hartung

You know, I think that the data we generated in our study has been useful for some of the advocacy groups in the multiple sclerosis community. So the National Multiple Sclerosis Society has been using it to try to, you know, advocate or perhaps political reforms or some other meaningful reforms in kind of how these things are reimbursed, things like that. Drug prices has been in the news quite a bit over the last several years, and now even more with the election season in full tilt. And so I think a lot of the candidates are talking about potential solutions to the issue.

From the patient's perspective, they're in a real quandary in a sense that even a sharp move with the Affordable Care Act to a lot of high deductible, high cost sharing plans where if your monthly cost of a MS agent is $5,000, you pay 20% of it until you hit your deductible. You know, that's $1,000 at the pharmacy, and that's a pretty big out-of-pocket cost that you face. So I think that there's some, you know, movement in the advocacy groups to try to…especially working with insurance companies to make sure that access is open because these medications are incredibly individualized. And there's not really good predictors of who will respond to each type of medication, and they're all different. Some of them are administered subcutaneously, intramuscularly, orals, and so there's some patient preferences that fall into play here as well as the price. And so I think there's been some movement and some discussion making sure that access to all the agents is relatively easy for patients.

But from a solutions to the pricing situation, you know, I think we're still kind of in discussion phases about what we can do as a country to kind of deal with this issue because it's not exclusive to the MS drugs.

MSDF

So what's next with you? Are you following up on this?

Dr. Hartung

So from our perspective, the group that I worked with, the two neurologists' project, we just submitted a grant, well, it was in January, that we hope to be competitive and hope to get that's looking at how these high drug prices actually affect patients in terms of their medication taking and potentially adverse outcomes because they're not taking their medication. Either they're hitting access restrictions from insurance companies or they just can't afford or have problems with the cost sharing or something like that, and so trying to quantify how this is affecting patients. And so from a research perspective, I think that's kind of our next move.

My colleagues, my two neurologist colleagues, they're really active in kind of speaking with representatives at the state about the issue, bringing it to increased visibility from our elected officials as well as making sure that the MS Society is aware of kind of the current status of the pricing trajectory. So we've been updating our graph that we published as new agents come online and things like that.

MSDF

Can you give us a couple of the updates you've made since the study?

Dr. Hartung

They haven't been dramatic, but there's been a couple new agents that have been approved. And I guess most notably is that the first generic drug for MS was approved, I believe, last April. So a generic for Copaxone came online. I think there's two manufacturers of it. When it came online, there was one. And so I think it was priced just modestly lower than the brand name Copaxone. But something interesting also just dealing with Copaxone, which is the number one MS drug in terms of sales, so when Copaxone lost its patents and lost its kind of patent disputes, in preparation for that, Teva released a different formulation of Copaxone.

So Copaxone is traditionally a daily injection. And so they released a three-times-a-week higher strength injection and basically switched everyone from the once-a-day to the three-times-a week 40-mg injection. And so I think a large proportion of patients who were originally on the once-daily Copaxone were switched to the 40-mg three-times-a-week Copaxone. So that really to some extent mitigated if there's any sort of savings due to this new generics in the field, kind of really mitigated any kind of savings due to the new generic as most people are now on the 40-mg three-times-a-week product. And the generic is not substitutable for the 40-mg three-times-a-week product. So that's a very common tactic in pharmaceutical industry approach to try to like sustain their franchise with a particular drug that's going off patent.

But the big questions are the ones that don't have a good answer. Essentially, what do patients do about this? What do we do as a society to deal with this issue? And you know, there's been proposals that have been put out by different elected officials and other folks about, you know, we should allow Medicare to aggressively and directly negotiate with pharmaceutical industry on price. We should allow importation of medications from other countries, similar industrialized countries like Canada. So the United States pays by far and away the highest prices than any other country in the world. And so many people think that we should be able to import these drugs that are the same drugs that are going to Canada into the United States. You know, some people suggest that there should be some sort of forms of price control. You know, maybe medications shouldn't be allowed to increase 10% a year or something like that.

And so all of these are being kind of discussed and played out and the pros and cons are weighed. And whenever you talk about limiting price increases, the usual response you get from industry is that any constraint on the amount of money that they're able to make and the profits that they're able to make for their shareholders is going to have some sort of effect on kind of future innovation potentially. Whether that comes to bear or not is unclear, but that's usually the number one response you get is that we need to have these high profits in place because it's an incredibly risky endeavor that we're doing. Only a very small proportion of drugs that are under development actually make it through the developmental process and are approved and make it to market. So any constraint on profits is going to have an effect in terms of future innovations and future breakthrough medications and things like that. Incentives are a big…they are real. And so that is something that needs to be weighed carefully in kind of any solution, essentially. I don't think it's the best solution, but just people are talking about a wide variety of things, I think.

MSDF

I appreciate your raising all these issues and going through the study. Is there anything else that I haven't asked that you wanted to add or emphasize as take-home lessons? Something to mitigate the rage, I don't know… [laughter]?

Dr. Hartung

Yeah, well I mean there's been a lot with all this, you know, the Valeant Pharmaceutical issue and the other company, Martin Shkreli guy who's castigated for increasing the price of this drug for toxoplasmosis by like 5,000% and buying the company and jacking up the price. That's a separate phenomenon of what is happening. But I think the outrage over that type of exploitation of the dysfunctional pharmaceutical market kind of masks and kind of hides the other issues that are happening on a consistent and aggressive basis in terms of just regular 6% to 10% increases in price on a year-to-year basis for drugs that a lot of people use, like drugs for diabetes or MS products, cancer agents, things like that. And so, you know, you have these really highly visible cases of really dramatic increases that are kind of morally outrageous. They draw your attention from the real and kind of moderate but aggressive and year in, year out, increases that are seen across the board in a lot of different agents. And that's where our focus should be essentially.

MSDF

That's helpful. Well, thank you so much.

Dr. Hartung

Yeah. My pleasure.

[transition music]

MSDF

Thank you for listening to Episode Ninety of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Carol Cruzan Morton. Msdiscovery.org is part of the nonprofit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is Vice President of Scientific Operations.

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

[outro music]

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

For Multiple Sclerosis Discovery, I'm Dan Keller.

[intro music]

Host – Dan Keller

Hello, and welcome to Episode Eighty-nine of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller.

Today's interview features Dr. Charity Evans, assistant professor of pharmacy at the University of Saskatchewan in Saskatoon, Canada. After a drug is on the market, systematically evaluating hospital admissions and the reasons for them can add new evidence for its effectiveness or adverse effects. By using clinical data from the British Columbia MS database and linking it to health system databases for MS patients, Dr. Evans evaluated the effect of beta-interferon on hospital event rates compared to those not on beta-interferon. She tells us what led up to this study.

Interviewee – Charity Evans

This was part of a larger study that was looking at long-term effects of beta-interferons, and we wanted to see if there was any impact of the interferons on hospitalization rates.

Interviewer – Dan Keller

And what did you do to look at it?

Dr. Evans

So we used data from two different sources in British Columbia. We had a clinical data set that has collected clinical data on patients since 1980, and then we linked that with health administrative data in BC; so we were able to get information on individual’s hospitalizations as well as the drugs that they were taking, and we used that to see if there was any effect of the beta-interferons on their hospitalization rates.

MSDF

And this was per patient per month or year, some time frame?

Dr. Evans

Yup. We actually looked at each individual patient in this study on a monthly basis; and so we each month said did you have any hospitalizations this month, yes or no, or how many did you have? And then we looked at their drug exposure, and we did that in two different ways; so we looked at were you on drug at that time that we were measuring you – so monthly – and we were looking at cumulative drug exposure, so how much drug had you been exposed to prior to that time, as well.

We actually found that there wasn’t any differences between the people who had been exposed to beta-interferon either currently or cumulatively compared to those who had no exposure to beta-interferon on the hospitalization rates.

MSDF

But what about any individual outcomes?

Dr. Evans

So with a secondary analysis, we also looked at specific reasons for hospitalizations, and we did find that there did seem to be a beneficial effect of the beta-interferons on hospitalizations related to respiratory diseases; so those individuals who had a higher cumulative exposure to beta-interferon over time actually had less hospitalizations for respiratory diseases.

MSDF

Does that take into account both infectious diseases as well as anything respiratory, like COPD or any other things that would affect the lungs?

Dr. Evans

Yup, that includes all of them. We did look at kind of the specific diagnosis for these patients and the majority were respiratory infections, so things like pneumonia or influenza.

MSDF

Do you have any idea what might account for that?

Dr. Evans

We have two thoughts. The first one is because the majority of hospitalizations were due to infections, we know that the beta-interferons have antiviral activity, so we thought is it this kind of an antimicrobial or immunoregulatory effect that the interferons were resulting in these lower hospitalization rates. And then the second one is a far less scientific thought, but we also wondered if people who are on drug, are they seen by healthcare professionals more regularly than someone who isn’t, and if that’s the case are they receiving more messages about preventative strategies for these types of infections; so when it’s flu season, are these people hearing more about the flu shots and getting a flu shot more than someone who maybe doesn’t see a healthcare professional as much?

MSDF

Could the interferon, because it’s working on their MS, have any beneficial effect in terms of neuromuscular function of respiratory muscles?

Dr. Evans

That one I wouldn’t be able to comment on specifically yet.

MSDF

Can you sort of dissect this by looking at patients on other disease-modifying therapies, which if they had the same reduction in respiratory might say that it’s not a direct antiviral effect but could be neurologic or healthcare access?

Dr. Evans

Yeah, that would definitely be the way to do it. This study specifically looked at the interferons; again, that was how the study was designed, but for sure if you included glatiramer acetate, as well, or some of the newer agents. At the time of this study for sure we didn’t have enough long-term data on the newer agents to be able to include them, but that’s certainly something that we’d be looking at in the future.

MSDF

So where do you take this in the future?

Dr. Evans

So we are, as you suggest, wanting to look at the newer agents and seeing if there is any impact of that, as well, so that would probably be the next step that we would do.

MSDF

If it were a direct antiviral effect, wouldn’t you expect to see it on other viral diseases? But I guess they’re much less common so events might be less.

Dr. Evans

And this might just be a complete chance finding, as well. Respiratory infections are more common in MS to begin with, so we didn’t notice it with other types of infections. But this is a secondary outcome so we weren’t looking specifically for this, so it might be something that if we tease out a study that that was a primary endpoint we might find differences, as well.

MSDF

If there was no overall effect on hospitalizations but there was a lower level of hospitalization for respiratory problems, was there an increase in other things that accounted for this zeroing out?

Dr. Evans

We didn’t see any statistically significant increases in any of the other areas.

MSDF

Sort of the difference between mortality and all-cause mortality, I’m sort of thinking, in the same way that you don’t want to prevent one and raise the other.

Dr. Evans

Right, yeah. You know, our findings did kind of coincide with right around the time where the 21-year followup of the initial pivotal trials of the beta-interferons came out where they did show a lower mortality related to respiratory infections, as well. Our findings kind of fit with that, as well, but as for the specific reason why I can’t say for sure.

MSDF

Can you reach any conclusions or recommendations?

Dr. Evans

Well, we didn’t see a beneficial effect of the interferons on hospitalizations, but I think it was also reassuring in that we didn’t see a spike in any kind of hospitalizations, or we didn’t see one particular type of hospitalization occurring. And so I think that is a good sign that there don’t seem to be any serious long-term effects or adverse effects that are happening with the interferons. So this is just kind of another, I guess, support for that, that these seem like they’re pretty safe drugs over the long term.

MSDF

Very good, thanks.

Dr. Evans

Thanks.

[transition music]

MSDF

Thank you for listening to Episode Eighty-nine of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Carol Cruzan Morton. Msdiscovery.org is part of the nonprofit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is Vice President of Scientific Operations.

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

[outro music]

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

For Multiple Sclerosis Discovery, I'm Dan Keller.

Full transcript:

[intro music]

Host – Dan Keller

Hello, and welcome to Episode Eighty-eight of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller.

You may have heard of transcranial magnetic stimulation, a treatment for migraine, neuropathic pain, and treatment-resistant depression using an electromagnet positioned on the scalp. Dr. John Hart, a professor of neurology and neurotherapeutics at the University of Texas Southwestern Medical Center in Dallas, is now testing another electrical technique called transcranial direct current stimulation, or tDCS, as well as alternating current to improve cognition in brain disorders, potentially including MS. An even more directed form, called high definition tDCS, allows more precise targeting of brain areas. The experimental procedure involves placing electrodes strategically on the outside of the head. We spoke in his office about how he's going about developing the technique and how it may eventually be combined with other therapeutic modalities.

Interviewer – Dan Keller

You're working in transcranial direct current stimulation. Basically, what is it; how does it work or be applied?

Interviewee – John Hart

tDCS is short for that. You'll have an electrode – actually it's a sort of small doughnut, so it's not such electrodes that people think of tiny little electrodes – and you place one on one part of the scalp area, and then another part, and you're basically going to pass current through the head in a sort of diffuse, generalized way, not very specific, from that one electrode to the other.

Recently, a new sort of area has been developed, a new cap system approach called high definition transcranial direct current stimulation. It's an EEG cap with EEG electrodes on them, and you can pass current out one electrode and draw it in a variety of other electrodes. So you can target it to specific areas where it's coming out, and you can also direct it as to where it goes through to multiple, depending on how specific or not, brain regions that you're going to have the electrode come out. So if you want to hit one spot, you can go out one and bring it in its surrounders and keep all the current there, or you can go from one place to another. And in some instances, we're able to throw it – sort of like throwing your voice – down the deep structures and sort of hit those as a way of stimulating.

The other part about it is the direct current part. We also do alternating currents, or HD TACS, and we can do frequencies and other things, too. So I feel that this has got a fair amount of promise and flexibility as a way to externally stimulate brain areas pretty safely. It does a little tingling to your scalp kind of side effects in terms of application.

MSDF

What kind of currents and voltages does it involve?

Dr. Hart

Right now normally in tDCS in the big things, we do 2 milliamps ballpark. We find that 1 milliamp is about where we're functioning now at the high definition, and right now we're doing studies with it where we're playing around with the amps and different frequencies to see – since it's relatively a new technique – what sort of effects you get. So … it's so new there's not a ton of papers out about it for me to tell you where we're going to land, will there be a dose-response curve? We're doing those studies right now.

MSDF

You've said that you’re interested, in general, in cognition across all sorts of brain disorders—Alzheimer's, MS, others. What's the hypothesis for using this kind of stimulation?

Dr. Hart

Well, in my primary research area I do word retrieval and knowledge retrieval and storage, so we've mapped out in that example a circuit of the pre-SMA, the pre-supplementary motor area, and the caudate and the thalamus that's involved in retrieving a memory. So when I say desert and humps, does that make you think of a specific object? When camel pops into your head, we mapped out with fMRI, EEG depth, and electrodes this sort of electrical pattern of that retrieval circuit to effectively pull up that memory. So the way we've been doing it, we came up with this circuit in normal people, and we've seen certain disease states where it's dysfunctional, and MS happens to be one of them. So we're directing, right now, our current to the pre-SMA and trying to stimulate that circuit to hopefully have a less functional circuit become more functional, where it can pull out the signal to noise and fire off the right rhythms or get their rhythms in a correct pattern that are not there.

Psychiatry's done a lot better in terms of treatments, because a lot of the disorders are based on neurotransmitters and neurotransmitter states, that a drug will affect those neurotransmitters, and it hits all the areas, because it's more the transmitter than the place. Cognition has a lot to do with place and connectivity. Drugs, we've not got a ton of them as the primary cognitive treatment because they don't go to a specific place, and they don't effectively change that specific area's connectivity and/or its links.

I have a big study we just finished with RTMS [repetitive transcranial magnet stimulation] in PTSD [posttraumatic stress disorder]. I look at the fact that having worked as an electrician of cognition for years, that that's what the circuit is, and the best way for me to change cognitive status in the way that it's lined up its focal networks is probably not showering a brain with drug that won’t go to specific areas but maybe targeting things like electrical and magnetic current.

MSDF

In terms of MS or other diseases, have you done any clinical studies so far?

Dr. Hart

So we're right in the middle of doing some MS patients preliminarily. And I don't get excited easily – I'm normally a pessimist, I think, at heart for these things. We've had some encouraging results in having people not on meds or who have failed meds or not had a response to meds that we've looked at retrieving memory in both word retrieval and in episodic memory retrieval and seen some improvements that have been relatively reasonably long-lasting from my point of view, lasting over months. But we've only at this point done about 5 or 6 people and we're enrolling more folks. We had a grant proposal in and we needed to get more folks to do a bigger trial. We're doing some placebo and then add people later to also see how much of this is a fair sort of setup as a placebo effect versus not. So we're advancing getting more and more folks into those stages now. And we've tried a few folks with TBI [traumatic brain injury].

MSDF

How long do you apply the treatment. Is it a one-shot deal and what's the residual effect? You said you've had benefit up to months, is that from a series or from just once?

Dr. Hart

We're doing one-shot now as a way of figuring out dosing and effectiveness, since it's a relatively new device. The way we're doing the treatments for folks is to do 20-minute sessions and 10 of those over a 2-week period. So once a day, 20 minutes, for a total of 10 sessions. And that has seem to have been from animal studies and some other folks in the literature reasonable time and reasonable number of sessions at this point. We're going to figure out and look at more about adjusting dose, dose response, will we need boosters if it starts fading, and things like that. Its affect fades, because in essence these folks are not treated with modafinil or stimulants that we're doing this, so we're not doing it in conjunction with that. So they're not receiving what are typical cognitive treating medications in MS. So that's a plus side, and that we haven't had any serious any sort of residual side effect things at this point.

So if it lasted several months and you had to reapply a booster thing, compared to taking amphetamines or some of the other pro-amphetamine drugs, I think the upside is reasonable enough to say that compared to that, it would be a reasonable issue if you came in 4 times a year if that's what we need to do. But we'll see as we keep following folks.

MSDF

If it works as you said, kind of separates out the signal from noise, essentially boosts the signal, the signal is gone when you turn it off or when someone leaves the treatment room. So what do you think, something's happening biochemically, or what's it doing that gives you a long-lasting effect?

Dr. Hart

When we just finish our RTMS trial for post-traumatic stress disorder, one of our interesting findings was the length of time, or the time when the effect lasts, or how long it lasts and continues. So there are some studies on electrical stimulation in animal models that suggests that what it does is set up a state called meta-plasticity. And the meta-plasticity in the animal models support the fact that long-term potentiation and synaptic potentials that can be set up down the road are actually benefited from the electrical stimulation. And that's what's encouraged us a little bit looking at stuff to see why these things last, because the first thing always like a single-shot, it fades off, it fades away.

Luckily, for some of this stuff we have some guidance from animal models. And this meta-plasticity phenomena has been noted for a continue – or delayed almost – effect of when you see improvement because of this. I think it's a state potential change that long-term potentiation can occur down the road. That's our best guess at this point.

MSDF

You said besides direct current stimulation, you're also trying alternating current. With a direct current, you probably would not get anything analogous to a magnetic stimulation because you wouldn’t set up a magnetic field. Do you see differences between your direct current stimulation and your alternating current stimulation?

Dr. Hart

We sure have – and I must admit none of this has been published yet because we're trying to set parameters. Initially, the enthusiasm for alternate current stimulation waned a lot, I think, for folks for any of these things, because it didn't seem to be nearly as effective as direct current. And I think as a lot of this stuff initially was done in normals. And I'm not so sure that when you have patients with a disease state, depending on what the disease state is, that I'm willing to sort of say that alternating current is not necessarily going to be useful or not. Also, this is very directional, so here's anode and cathode. So you can take the same current, same electrodes, change the directionality and get different effects. And typically people that found those things in the motor system were pretty noticeable.

In cognitive systems, we haven't seen that as much, that when we flip the direction of the current, that we're getting the opposite effects—so instead of enhancing a performance in something, that we're knocking it out. So I think once we look at sort of these things, every new approach has to be taken really as a start from scratch, do the hard work of just what we're doing, change the amplitudes, change the parameters, change the direction in a nice, safe way in single shots, and which we've been doing, and then record pre- and post.

We do a lot of electophys measures, but also cognitive measures and other sorts of measures to see how each one of these effects things, and do we have something that I would hope one day I'll be writing electrical prescriptions. And I'll say you should get F4 to CZ current at 1 milliamp or 0.5 milliamps, or whatever I wind up doing, for 10 sessions, 20 minutes. Or, no, my god, look at this, we've got to go from here to here at a different milliamp. Once we start looking at that, I think to me also frequencies are very important; can I send different frequencies instead of milliamps. We're going to discover a lot of different things work differently, especially in diseases that are not a homogeneous thing.

Brain disease is not like liver cancer. Hepatocytes, it's like how many hepatocytes are not working and how big is the tumor? No, not having a good thalamus is very different than not having a functional motor cortex, you just see entirely different results. So I think it's going to be a lot more complicated, but I think doing it in a systematic way in normals, and then applying it to certain disease states gives us our best chance at coming up with primary or as adjunct treatments to other ways we're going to be treating diseases that have cognitive problems.

MSDF

It doesn't seem surprising that the polarity wouldn't matter, because not all the neurons, dendrites, and synapses are lined up in one direction; they're going in all different directions, so even their polarity is different. It seems like zapping it in one direction for one, but the opposite direction for the other anyway.

Dr. Hart

We've actually done stuff with EEG measures and fMRI measures, and done these things called Granger causality models. So how much does, say, one time point predict an activation or a change in the other time point? And in an area that we thought was really this guy is telling that guy what to do, we found that most of those were predominantly a lot of two-way interactions that are constantly going on, and there's a lot of feedback between these systems.

And I always try to think like neurons and think electrically, and I can do it for about a couple hours and then my head starts really hurting. And in reality, I think the simplistic: Turn this light switch on and that you have a serial processing circuit is not really how electrically two neurons are always working together, or talking to each other, or keeping a tone or a level up. So I think you're right, I learn a lot every day. It's been sort of a cool job to figure out, yeah, that makes sense, because really it's an interactive set of neuronal firings.

MSDF

Do you see any role for combining it with drugs that have ionotropic effects?

Dr. Hart

Yeah, I do. And the other part of that is going to be really, to me, which I think has been a problem with a lot of approaches to cognition and treating them, the timing of when and how you add different therapies together are going to be very, very important. Even now to say, all right, let's say I want to do a behavioral therapy with HD [high definition?] tDCS, well do you do it during it, do you do the HD tDCS continually? Do you pre-prep the brain by doing that first, and then doing cognitive rehabilitation strategies and therapies? I think we glibly just put things together without thinking that there might be an order to this. So right now we're looking at what's called state changes. We're not the first folks to do this, but some people say before you do tDCS, and that's before this HD stuff, you do a little RTMS first to set the state of the neurons in that area so they're more receptive to whatever you're going to do with the tDCS.

MSDF

Just to be clear on it, RTMS is repetitive transcranial magnet stimulation.

Dr. Hart

So I think we're looking at kind of like, you know what, you get your pre-meds before you get your chemo so you don't vomit or do this or that. We might be finding ways that electrically how we're going to, or even you use meds prior to a treatment electrically, or vice versa, that that timing is going to be where the money is in terms of working out what are going to be the most effective therapies.

MSDF

What have we missed? I realize it's still pretty early, but is there anything important to add?

Dr. Hart

I think the way we've done it is not going to always be available, in that we came from a circuit that we worked out, and we have an idea as to what we were trying to do. And we're measuring all these brain rhythms as outcome measures, so I know when I'm supposed to see alpha and beta rhythms to do that. And I think what's going to happen is we're not always going to have these circuits, we're going to have a spot. Like we've talked a little bit, shall we try to hit the hippocampus? And what other diseases would you do these things in? And the question's going to be when you're doing that, or doing that as a general approach, how do you smartly do it, when you really are not sure about the circuit?

We don't have a ton of really well worked out cognitive circuits in an active state of doing things. We have a lot of functional connectivity rest states, and you say I'd like to amp up that connectivity. I don't know what that does functionally, if you electrically take a rest state that normally is when your eyes close and add current to it. So I think while we've targeted this in the two areas that we're using electrical therapy in, post-traumatic stress disorder and this, and the things we've chosen, we built it off of normal studies.

The things we've got to be careful about, thoughtful about, and open-minded to at the same time about, is what if we want to treat something different than this? We want to do working memory, we want to do episodic memory, we want to do frontal behavioral problems. And if we don't have a circuit, try our best to get the most reasonable pre/post measures. Do single shots just to see what it does in a transient state, and then sort of work our way through the fact that at least a reasonable pre/post model and start thinking of this not as one-size-fits-all, but may be 0.5 milliamps, maybe TACS, maybe pink noise, maybe whatever sort of way you want to deal with it. It's going to take a lot more thought, I think, than people might casually say, hey, got some electrodes?

I mean, what bugs me right now is you can set up your own tDCS device off the internet, one of them using a car battery – 2 pieces of metal and some wire. And I highly would tell all those out there, which I know none of your listeners, don't do that. So when people started sort of exploring around in what they're going to do, I hope as we take this field further that we need to do it in a systematized fashion and a thoughtful way, because there's a lot of information you can get when something doesn't work. So you know what, I didn't change a thing here when I did this.

Well, I would like to know that, you know, is somebody else trying to do it, and try to collect this information that might be useful to other people trying to do things. Saying, you know what, we did this electrodes, these are these things in normals or whatevers and didn't get a response, to try to come up with a way that we've got to take it for the fact that it's like a med. It's going to have schedules, it's going to have doses. So if you're taking it twice a day at 5 mg or 6 times a day at 40 mg, working all that out is going to clearly need to be done in a reasonable, thoughtful way.

MSDF

I appreciate it, thanks.

Dr. Hart

Oh, thank you so much, I really appreciate your interest.

[transition music]

MSDF

Thank you for listening to Episode Eighty-eight of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Carol Cruzan Morton. Msdiscovery.org is part of the nonprofit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is Vice President of Scientific Operations.

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

[outro music]

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

For Multiple Sclerosis Discovery, I'm Dan Keller.

[intro music]

Host – Dan Keller

Hello, and welcome to Episode Eighty-seven of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller.

Animal data, laboratory studies, and even some human evidence suggest that restricting caloric intake may have a salutary effect on diseases that involve inflammation, possibly including MS. I spoke with Dr. Ellen Mowry of Johns Hopkins University at last fall's ECTRIMS meeting in Barcelona about the rationale for testing caloric restriction in patients with MS and a study that she's carrying out in this regard.

Interviewee – Ellen Mowry

Laura Piccio and Anne Cross at Wash U, among others, looked at calorie restriction in a mouse model of MS, EAE. And they were able to show that reducing calories prior to the disease reduces the disease and/or its severity. And there are a lot of other in vitro data, other mouse models, and even some human data from other patient populations suggesting that intermittent fasting or intermittent calorie restriction not only reduces inflammation, but may improve oxidative stress handling in mitochondrial function.

So we were really interested in whether the ecological observation that the incidence of MS increasing sort of is tied to the same time period in obesity epidemic and that Langer-Gould has showed, among others, that childhood obesity, especially in girls, seems to be a risk factor for MS. So could we be just eating too much, and is that sort of contributing to a burden of MS risk or to a worse prognosis?

So we're doing a trial—it's funded by the National MS Society—of a controlled feeding trial where we're randomizing people to either continuing a sort of traditional western diet at the same level of calories they would need to maintain their current weight; to eating that diet most days, but two days a week having only 25% of their caloric needs for that day; or to a group where that same number of calories or percentage of calories is restricted, but spread out over a week. So we should be able to look at the relative impact of just weight reduction, for example, versus the timing of calorie intake to some extent.

And we're also really curious to see like when we're done with the early phase of that study, which is eight weeks and we'll be providing foods to people, whether or not patients can sustain that diet afterwards for a longer period of time. Because I think there's really great building rationale for evaluating diet as a potential modifier of the disease. But the other side of studying diet and dietary modifications in people with MS is that we don't know how to encourage people and help them participate in meaningful lifestyle changes that are sustainable. So I think we need to look at that carefully as well.

Interviewer – Dan Keller

Is there any gradient of incidence of MS by BMI?

Dr. Mowry

So Annette's study really showed a pretty strong impact of adolescent obesity in girls on MS risk with I would think about a fourfold increase in the odds of developing MS if you were an extremely obese adolescent girl compared to a normal or underweight. And other studies have looked at this as well and shown a very similar set of results. So I would call it sort of a fourth environmental risk factor for MS. I think enough studies have shown a similar association that we can consider that a likely risk factor at this point.

MSDF

In your study on caloric restriction, are you giving any thought to the composition of the diet? Or are you going to be heavy on carbohydrates, minimize fats, the reverse?

Dr. Mowry

So we're actually aiming for the 50th percentile of the typical American diet for all the macronutrients, fat, carbo, and protein. The reason is we really want to study the concept of caloric restriction in isolation, and in particular, in a pilot study where you don't have a huge number of people, you can't alter too many things, or there's going to be too much noise and you're not going to know what is what. So certainly I think looking at the macronutrient content of the diet as a separate study would be very interesting and informative, but in this study we're actually trying to control, to just sort of keep it at like what typical Americans are eating. So we're really isolating the effects of the timing of calorie and the amount of calorie intake.

MSDF

What have we missed or is important to add or interesting?

Dr. Mowry

I'm just really encouraged, I think, that the MS community is getting more interested in diet and even exercise and other lifestyle modifications that might be important for people with MS. And Ruth Ann Marrie's work looking at comorbidities in MS and demonstrating that people with MS, who are otherwise healthy, are at lower risk of bad outcomes than people who have comorbid illnesses like diabetes and hypertension and that sort of stuff means that we maybe should be focusing on promoting the overall health of our patients, too, to sort of prevent or minimize the effect of some of these comorbid illnesses. So I think it's really a great step that we're starting to think about investigating diet and exercise in our patients.

MSDF

Good. I appreciate it. Thanks.

Dr. Mowry

Thank you very much.

Full transcript:

[transition music]

MSDF

Thank you for listening to Episode Eighty-seven of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Carol Cruzan Morton. Msdiscovery.org is part of the nonprofit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is Vice President of Scientific Operations.

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

[outro music]

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

For Multiple Sclerosis Discovery, I'm Dan Keller.

Full transcript:

[intro music]

Host – Dan Keller

Hello, and welcome to Episode Eighty-Six of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller.

A hallmark of multiple sclerosis is a new brain lesion. The active inflammation normally goes away in about 4 to 6 weeks, disappearing from contrast-enhanced detection by MRI scans. More recently, in some people with MS, researchers have found smaller longer-lasting inflammatory lesions outside the brain, in the surrounding lining called the leptomeninges, as well as evidence that they may play a role in progressive disease. The tiny compartments are associated with more severe disability, worse outcomes, and nearby gray matter demyelination.

Dr. Pavan Bhargava, a neuroimmunology fellow at the Johns Hopkins University MS Center in Baltimore, Maryland, has started a phase I trial to slow progressive disease by targeting the B cells in these follicles. He is testing an anti-B cell antibody called rituximab, using the drug intrathecally—that is, injecting it directly into the cerebrospinal fluid of patients with primary or secondary progressive MS, so that more of it reaches the inflamed pockets in the brain lining. We spoke at the ECTRIMS meeting last fall in Barcelona, where he described to me the rationale for this experimental treatment approach.

Interviewee – Pavan Bhargava

In 2004, what was noted was that in autopsies of MS patients, there were collections of lymphoid cells in the meninges, and these aggregates of lymphoid cells were noted to abut areas of the cortex that demonstrated demyelination. So this suggested that possibly these collections of B and T lymphocytes that were in the meninges might be driving some of the cortical demyelination that is seen commonly in patients who have progressive MS.

So the idea behind using rituximab intrathecally is that we want to, first of all, get as much rituximab as possible into the CSF [cerebral spinal fluid] and into the brain, because when we give rituximab IV, less than 0.1% usually gets into the CNS [central nervous system]. So we're trying to target the B cells that are found in these lymphoid follicles, and we're trying to get as much of the rituximab into the CNS as possible. So that's the rationale behind using intrathecal rituximab in progressive MS patients.

Interviewer – Dan Keller

Do the patients you're selecting just have visible leptomeningeal lesions, or do they have to have abnormal CSF – IgG elevated or oligoclonal bands – or how are you selecting them?

Dr. Bhargava

So in our trial, we are selecting patients using an MRI finding that was described now a couple of years ago that on a time-delayed post-contrast flare image, in about a third of MS patients you can actually see contrast-enhancing lesions, not in the brain parenchyma, but actually in the leptomeninges. And a recent paper from the NIH showed that in a couple of these patients who had contrast-enhancing leptomeningeal lesions, when they came to autopsy they could identify clusters of lymphocytes and macrophages that corresponded to these contrast-enhancing leptomeningeal lesions. So in our study, we're basically screening progressive MS patients with an MRI, and are only including patients in this study who do have evidence of these leptomeningeal contrast-enhancing lesions, because we feel that this is a marker of leptomeningeal inflammation in these patients.

MSDF

And have you run any patients yet?

Dr. Bhargava

So we have 5 patients currently in the study, of whom 4 have actually completed their treatment phase of the trial. And our goal in this study is to enroll 12 patients. And the primary outcome is safety. So, you know, we want to know that using rituximab intrathecally in MS is safe. But our secondary outcomes include looking at the change in the MRI lesions that we noted at baseline, and then we're also going to look at the change in immune populations in the CSF and some biomarkers for axonal damage and chemokines that are associated with these lymphoid follicles.

MSDF

Are these lesions similar to ones in the brain parenchyma that come and go, or will you be sure that your treatment is what caused any difference?

Dr. Bhargava

So these lesions that we note on the MRI in the meninges, unlike lesions in the brain parenchyma, where you note contrast enhancement when they're new and active, and then about 4 to 8 weeks later, they stop taking up contrast, the lesions in the meninges continue to enhance for years. So there's data that these can continue to remain the same and enhance for over 3 years. So that's really why we decided to use this as a secondary endpoint, because we have not seen changes in these lesions over time. And so if we actually saw a change, it might suggest that it was secondary to our intervention.

MSDF

Since this is a phase I trial, do you have a control group, or you're just looking at the ones you're treating?

Dr. Bhargava

Yeah, so because this is a phase I trial and the primary outcome is just safety, this is open-label, and so everyone in this trial is going to receive intrathecal rituximab.

MSDF

When do you expect to see any results, or have you?

Dr. Bhargava

We will be analyzing all this data once we've accrued the patients, and we're hoping to complete recruitment in the next 3 to 4 months, and then we follow all these patients for a year. So probably at some time towards the end of next year [2016] we should have results from the trial.

MSDF

Is this a test of concept, not only of rituximab but of what these leptomeningeal lesions mean?

Dr. Bhargava

So yes and no. In a way, there's a proof of concept because if we were to see changes in these lesions that otherwise remain really stable, that might suggest that a drug that could possibly deplete B cells makes a change in these leptomeningeal lesions. But it's also possible that perhaps B cells are not a sufficient target, or that we're not able to deplete B cells that are within these structures. And so, you know, there are some confounding factors that possibly could lead to this trial not being successful. But this is what we plan to look at is, if we actually see a change in these lesions, then to us that would be a kind of a proof of concept that rituximab might be able to effect these leptomeningeal lymphoid aggregates.

MSDF

Is there evidence that these aggregates are pathogenic?

Dr. Bhargava

There is evidence in terms of previous studies where they looked in autopsies in both primary progressive and secondary progressive patients. They found that people who had evidence of meningeal follicles had more cortical demyelination compared to those who did not. So that is indirect evidence that perhaps these follicles play a role in disease progression and may be pathogenic. We don't have direct evidence yet in patients who have been, say, prospectively followed to suggest that these lesions are causing damage.

MSDF

Are these aggregates solely B cell, or what else is there?

Dr. Bhargava

You know, these aggregates have B cells, but they also have plasma cells, they have follicular helper T cells, and they have follicular dendritic cells. So there are multiple cell populations that make up these follicles, and each of these populations produce factors that keep this follicle going. And so perhaps disrupting just one component of this follicle may not be sufficient, and we may need to then expand our targets and try to target multiple cell populations at the same time.

MSDF

I suppose, though, if you do interrupt the sort of chain of events, it may be sufficient to break one link.

Dr. Bhargava

Right. That's our hope with this trial is that taking out maybe one key player in this follicle might be sufficient to then disrupt this vicious cycle, but only time will tell.

MSDF

Is there evidence that lymphoid aggregates may exist in the meninges in people without any evidence of any disease?

Dr. Bhargava

We don't know the answer for that for sure, but in the study from the NIH, they didn't really see these contrast-enhancing lesions in healthy volunteers. So that would suggest that perhaps these are not found in healthy people without disease.

MSDF

I'm just thinking in terms of normal brain protective mechanisms, whether things like this fight off disease.

Dr. Bhargava

That really would need a study looking at the meninges in people who pass away from other diseases; in, say, not autoimmune diseases. And the reason why this is such a fairly recent discovery is just because when pathologists used to look at brains at autopsy, they would just rip off the meninges and throw those away and just look at the brain. So I'm sure this question could be answered, but right now we don't know. There is actually some emerging evidence that perhaps these follicles might be seen in other CNS immune diseases, for example, Rasmussen's encephalitis. There was a study from our center where they noted presence of possible B cell follicles in biopsy material from patients with Rasmussen's encephalitis, and so it's possible that this might happen in other autoimmune disorders. But this process of ectopic lymphoid neogenesis seems to happen mostly in autoimmune diseases, like type 1 diabetes or Sjögren's syndrome or rheumatoid arthritis, and so it seems to be related to autoimmunity.

MSDF

If this pans out what you're doing now, would rituximab be pursued, or do you foresee other monoclonals coming along that may be more appropriate to carry forward?

Dr. Bhargava

I think part of that would depend on what we see in this study, and if we don't see a robust effect then we might switch to a different target. And also, you know, we may want to target more than just the B cells. You know, there are other therapies coming down the pipeline, like anti-CD19, which targets a broader range of the B cell lineage, and then perhaps we might try to target like, say, plasma cells. So I do foresee that if we continue with intrathecal therapy, we would end up trying to use other monoclonals, as well.

MSDF

Is this a feasible technique in many patients, a wide array, or is it very specialized and would have to be restricted?

Dr. Bhargava

It is not really that difficult to perform, because we basically are performing a lumbar puncture and are injecting the drug through a lumbar puncture, and so it should be feasible. Of course, it is still an invasive procedure. However, if we really did see a benefit from this, then I think it would probably be worth that effort and risk.

MSDF

Have we missed anything, or anything important to add on the topic?

Dr. Bhargava

It's important to continue to try to understand how this process is affecting the brain and whether it's actually causing damage. And I think more studies looking at perhaps imaging to see how these lesions are affecting the brain parenchyma around them may give us more insights into how pathogenic these lesions are. And then I think from our study we might begin to understand whether we're able to actually make a difference to these lesions that we're seeing.

MSDF

Very good, I appreciate it, thank you.

Dr. Bhargava

Thank you.

[transition music]

MSDF

Thank you for listening to Episode Eighty-Six of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Carol Cruzan Morton. Msdiscovery.org is part of the nonprofit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is Vice President of Scientific Operations.

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

[outro music]

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

For Multiple Sclerosis Discovery, I'm Dan Keller.

Full Transcript:

[intro music]

Host – Dan Keller

Hello, and welcome to Episode Eighty-five of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller.

Many MS patients will require a change of drug therapy over the course of their disease, possibly because of relapse or tolerability. At last fall's ECTRIMS conference in Barcelona, I spoke with Eva Havrdová MD PhD, professor of neurology and head of the MS Center at Charles University in Prague, Czech Republic, about when and how to change therapy. I first asked her how she detects a need to change therapy because of a suboptimal response.

Interviewee – Eva Havrdová

It's very difficult to find the right solution for each patient, but as to our opinion, the best thing is to really start early treatment and monitor closely the patient. It means that you look not only at relapses or progression. It's too late. We also look at MRI after six months after starting treatment. And I think it is now quite proven that, if the patient has either relapse or new MRI activity, the response in the first year is suboptimal and the treatment should be already changed.

Interviewer – Dan Keller

So you have a very high suspicion?

Dr. Havrdová

Yes, definitely very high suspicion. And you can add some quality of life measures. You can add cognitive measures. You can ask the patient, what’s the level of fatigue. And of course, all this together brings you to the solution to change the treatment.

MSDF

Do you generally find that you will pick something sooner on MRI then by patient report?

Dr. Havrdová

Yes, of course, because the events on MRI occur 10 times more frequently. But on the other hand, as to regulations for reimbursement, I cannot change the treatment just based on MRI in our country. So definitely in the future, this will be an option. But we need more data to prove to the sick fund that it's really worth doing it because if you do these changes and find optimal treatment for patients early, then the patient stays at work, and of course, the cost effectiveness of the drugs increases.

MSDF

I suppose that depends on having a unified system, which is not built into silos. You know, when you get one payer here and one payer there; they don't care what's coming out of the other guy's pocket.

Dr. Havrdová

Yeah, yeah, of course. It's very difficult; and therefore, I think we need guidelines. And one of the ECTRIMS activities is to start working on some guidelines, and I hope next year we will have it.

MSDF

So what do you do when you find something that would raise your suspicion or prompt you to do something different?

Dr. Havrdová

We monitor the patient even more closely, in three-month intervals. And very often we see that the patient develops a relapse after some MRI activity occurs. So we can change the treatment.

MSDF

Do you often escalate the present drug? Or switch drugs immediately?

Dr. Havrdová

We have to start with injectables in our country, not with oral drugs, which is the mainstream now in other countries. And we hope we will also push our authorities to this strand because patients, of course, want orals. On the other hand, the safety of injectables is well-proven for more than 20 years. So for those especially who want to get pregnant, the safety is number one. And we try to switch as early as possible, because if another relapse comes, the relapse may be disabling, and we are just losing time in the brain of the patient. And as you know, here at ECTRIMS, the one day before, the health of brain was promoted in MS. And we would like to stick to this idea.

MSDF

So it sounds like you change drugs, not escalate the present drug?

Dr. Havrdová

The escalation means the change as well. So we try not to switch within the first line, but we want to see more effect. Just because of intolerability or some known adherence of patient on injectables, we can switch within the line if there is no activity of the disease itself. Or if there are neutralizing antibodies on interferon, we can switch to Copaxone. But on the other hand, it was now published, based on data in MS base, which is a big registry of real world data, that it's really worth escalating to the higher efficacy drugs because you can reach much better effect.

MSDF

Over the years, do most patients require some change?

Dr. Havrdová

Most of them do, though there are patients who are completely stable and not developing higher EDSS steps on injectables, but it's less than 25% of them.

MSDF

Is there any way to generalize and say what the time course is? Or is it so variable?

Dr. Havrdová

No, it's very variable. And we do not know if it is based just on genes or on environment or lifestyle changes the patient is willing to undertake. We do not know yet.

MSDF

So I don't know if you can generalize because each country is different, but do you have some scheme or algorithm in mind about how you would escalate therapy?

Dr. Havrdová

The problem is if the patient is not responding to the second line or higher efficacy therapy, because we then have to switch within that line. And we do not know if he doesn't respond to anything we have. We do not know what to do. So we cannot switch or jump from one treatment to the other after six months of treatment, because you have to allow the treatment to have an effect. So at least six or nine months is okay. If the patient is not responding, then you can jump to other treatment. But hopefully the patient will respond to the third or fourth treatment, because it's not without limitations.

MSDF

Is combination therapy every indicated?

Dr. Havrdová

Not yet. I have thought many years ago that neurologists are just reluctant to use combination therapies, but now there were some trials, and it's not showing that effect. So it's not like in oncology. Though the principle is so clear, that you can combine drugs with various mechanisms of action decrease, some side effects, and increase the efficacy. Oncologists do that. We don't have drugs in the multiple sclerosis with this potential yet.

MSDF

Right. In hypertension they've just assumed they're always going to have two or three drugs, and same thing now with diabetes and things like that. But I guess this would be a big conceptual breakthrough for neurologists?

Dr. Havrdová

Yeah, and doesn't seem to be today's issue.

MSDF

What has been tried in combination?

Dr. Havrdová

The first combination which was tried was natalizumab and interferon. And it seems that it didn't work. And then, of course, it was also a small trial, natalizumab plus glatiramer acetate, and nothing just to safety was, of course, seen that. And some others, but nothing really.

MSDF

When there's an acute exacerbation, do you overlap steroids with the ongoing drug?

Dr. Havrdová

Yes, of course. Yes. It was proven that it's safe, and it's okay.

MSDF

So there is a combination, but short-term?

Dr. Havrdová

Yeah, it's a short-term combination. And definitely it helps because all the underlying immunomodulating drugs do not work against the acute relapse.

MSDF

What have we missed or is important to add on the topic?

Dr. Havrdová

I think that neurologists have to be aware, and of course, pharmacovigilent. You have to know the mechanism of action of the drug; you have to know the adverse events possible and how to prevent them—how to monitor the patient to be safe.

[transition music]

MSDF

Thank you for listening to Episode Eighty-five of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Carol Cruzan Morton. Msdiscovery.org is part of the nonprofit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is Vice President of Scientific Operations.

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

[outro music]

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

For Multiple Sclerosis Discovery, I'm Dan Keller.

[intro music]

Host – Dan Keller

Hello, and welcome to Episode Eighty-four of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller.

People with MS take disease modifying therapies, or DMTs, for years. But is it possible to stop the drugs at some point or at least take a drug holiday? I spoke last fall at the ECTRIMS meeting in Barcelona with Dr. Ilya Kister, an assistant professor in the MS Care Center at the New York University School of Medicine. He has looked at various studies and registries that shed light on the question, and he discusses the utility and limitations of using observational data from big data sets.

Interviewer – Dan Keller

People know a lot about starting DMTs, but not about stopping. And, I take it, there's not much been looked at yet in terms of could you stop and what happens.

Interviewee – Ilya Kister

Yes, that’s a question that patients often ask, and clinicians certainly wonder about. Is it safe to stop the drug? When is it safe to stop it? And all the literature that I’ve seen on stopping the DMTs has basically analyzed the reasons for stopping them. The reasons for non-adherence—why did patient not want to continue—but there is very little data on actually what happened in terms of disease course. It’s just an observational study, you know. Do those patients continue to have relapses? Do they have more relapses or less? The only exception is natalizumab, where we have, you know, more than a dozen—probably two dozen—articles looking at what happens when you stop the drug. But that’s a little kind of almost an exceptional circumstance. There is a question of disease rebound and such. With the other drugs, very little to no data. So, so one wonders whether it’s an okay thing to do.

MSDF

What are the pros versus cons of stopping?

Dr. Kister

I think you can make almost equally appealing arguments on both sides. The arguments to continue the drugs, the main ones, are that relapses are unpredictable, and even though they’re less common as people age, we do see patients in practice, even in their 60s, who have relapses. And there was a recent study that showed that about 30% of secondary progressive MS patients have relapses. So, presumably, the drugs which work to decrease the risk of relapse would be helpful to reduce the risk of relapse even in those circumstances as well. But that’s not entirely clear, because they were never shown to be beneficial, truly, in the secondary progressive patients or in the older patients, because older patients are, by and large, excluded from all the studies. So we really don’t have any high-level data on these subpopulations.

So the reasons to continue would be to try to prevent relapses, even in older patients. And the reasons to stop would be that the relapses are kind of few and far between. It may be not worth the hassle, and maybe the disadvantages of continuing in DMT long-term outweigh the theoretical risk of decreasing relapse rates. So it’s in a clinical equipoise situation, as far as I am concerned.

MSDF

How have you looked at this issue?

Dr. Kister

This is just kind of our individual practice, and many people may agree or not agree with it. This is not really based on our studies, but generally speaking, patients after age 60 who haven’t had relapses or MRI activity for at least five years, I do have a discussion with them and kind of feel them out whether they’re interested in stopping or not. And the reactions vary widely. You know, some people are very attached to their drug. They feel like it’s helping them and protecting them and has done good for them, and they don’t even want to think about stopping. And some people are very tired from being treated for many years. They don’t necessarily see the advantages of it, and they’re very willing to consider stopping and take you up on the offer. They just need a blessing to do this, because the doctor says to stop. You know, there are people in between who are kind of vacillating and not sure. But this is a population that I would consider stopping the drug.

But now, about two weeks ago, we received the news that we have funding for study, wherein we’ll randomize patients. Some will continue on whatever drug they were on, and some will stop. And then this way we’ll actually collect, in a more rigorous fashion, the data of actually what happens to those patients. And that’s a study where the primary investigator is Dr. John Corboy from the University of Colorado in Denver. And there are six sites across the states that were approved for this, and where NYU is one of the six sites, and maybe a few more sites will be added. So this is our best hope, I think, to conduct, not a randomized clinical trial of starting a drug, but a randomized clinical trial of stopping a drug, which has been done in other fields, most important in oncology, a little bit in psychology, but not in neurology or in MS, as far as I know.

MSDF

But short of that, you've done a database study and looked at people who have stopped?

Dr. Kister

Yes, though that was a study that was just presented at this ECTRIMS meeting. And there we used a very large international registry called the MS Base, which has over 30,000 patients enrolled in it, so, and dozens of countries. And it's open to any investigator in the world who is interested, and he can contribute patient data. Obviously, it's patient consent, and many patients are interested in contributing their data to the registry.

So because the registry is so large, we were able to include for this study almost 500 patients who met our criteria, which were fairly rigorous. We required that patients be on some drug for three years; have no relapses for at least five years, because we want to exclude active patients; and be followed for at least three years. Three years is more than most clinical trials, which are one to two years. But we really wanted to see what happened to them this time. And we excluded people who went from one DMT to another within three months. So this was the crux of this study. We looked at this—485 patients to be exact—and we followed them. And the minimum was three years, but the median was almost five years.

And we found that in this population during this followup of almost five years, 36% of patients had at least one relapse. And 31% of patients had a confirmed disability progression, meaning three months apart they had a worsening of EDSS. And almost half of the patients have restarted a DMT, but not right after stopping, but two years or more after. That was the average time to restart. So that was the main kind of result. So when you talk to the patient, you try to kind of lay out the data for them, you know, this is the numbers you can use, I think. Even though somebody hasn't had relapses for five years or more, they still are at risk of relapses. And what we found was a predictor of relapses was age and EDSS. The younger patient and less disabled patients who we think are typically probably more in the relapsing phase, rather than in the secondary progressive phase, were more at risk for relapses. So for younger patients, I would be much more wary of stopping the drug, even if they have been relapse-free for years, than in an older patient. So that's one result of the study.

But there was a second component of this study which was interesting, I thought, wherein we compared the people who stopped the drug with the people who continued on the drug, and we matched them. There is a technique called propensity score matching. So we matched the people who stopped and the people who stayed. And the two groups were almost identical. All the parameters, like age, disability, how long they've been on the drugs, proportion of times they've been on the drug, their gender—very, very similar according to most of the variables. And we followed them through time, and the mean followup for both groups was about five years.

And we found, a little bit counterintuitively, that people who stopped the drugs did not have any more relapses than people who did not stop the drug. If you think that the drugs are protective, you will expect some effect; we didn't see any effect whatsoever. There was absolutely no effect.

But interestingly enough, the people who stayed on the drug tended to progress, to show confirmed disability progression, a little less. They were at less risk of disability progression, about 40% compared to people who stopped. So it's a little hard to interpret this data. It may be that the drugs actually have some cumulative effect and maybe continue, and that does delay disability progression. That would be a very favorable interpretation as far as clinicians are concerned and the rational to continue.

But it may be that people who stayed on the drug were really in some what we call unmeasured confounders. They had some reasons why they stayed, and they are not really entirely comparable to the people who stopped. Maybe they were a little more, for whatever reasons, considered to be more active by the clinician, and that's why they kept them on the drugs. So maybe there're intrinsically different groups with intrinsically different disability progression, and that is the reason for the finding.

So this is where we stand right now, and this goes to show kind of the utility and the limitations of using observational data sets. The utility is that we're able to basically run that kind of a pseudo-trial, if you will, comparing the stoppers and stayers, and run it for many years. We actually have data six, seven years after stopping the drug, which is almost not possible with randomized clinical trials. And we're able to use this data. In fact, to power the clinical trial that I talked about earlier, because we can predict how many people are expected to have relapses at this age and such. And the limitation that there are known unmeasured confounders, and that there're biases in who continues to be observed and who is not, and we cannot control for that without randomization.

MSDF

Now, from your study, it looked like people who had been off of a DMT for more than two years had a higher relapse rate. Is there any possibility of having a drug holiday? Or, when someone comes off drug, a silent insult happens that you only see later, so you really have to not give them a holiday?

Dr. Kister

Well, it's a hard question to answer. They had a higher risk of disability progression, not relapses in this study. The curves begin to diverge after about two years. It was more of a long-term effect. So, you know, one wonders. But the counter argument to what you are describing is maybe there's a cumulative effect, that you really have to stay on the drug for long periods of time in order to see. And if you stop and have a holiday, you kind of wash out that possibility. So the answer is, we really don't know whether it's okay or not to give holidays. It's definitely not okay in actively relapsing patients, especially if they're on strong drugs like natalizumab or even Gilenya or even interferon. That's pretty clear. So but as far as the patients who hadn't had relapses for a long period of time, we don't know. It remains to be seen.

MSDF

Is there a continuing effect of any drugs, such as monoclonals, like alemtuzumab, where you might get a tail effect even after stopping it, which would essentially be your accumulative effect?

Dr. Kister

I think that is, you know, a very important point that we talked about stopping the drugs, but we really have to specify which drug we're stopping. Because drugs like alemtuzumab have been shown to have an effect that lasts for four years or more. And I think at this conference they will show data for even longer term effect of alemtuzumab. I've seen some posters to that effect. So those drugs have an effect on the immune system that persists. Some chemo treatments as well, you know, a stem-cell transfer. It's not something you do every year; it's something you've done once, and you see the effect that lasts for a long period of time. So I think a lot depends on the mechanisms of the drug, you know, how long they're expected to affect the immune system for. Something like natalizumab that washes out within three months or so, and you don't really see, you know, effect on the receptor level than you'll be after about three or four months. We don't really…you wouldn't expect it to work beyond that time, and it really doesn't. It only lasts that long. And other drugs, there is a sustained loss of T cells and B cells for a long period of time, and perhaps that's why there's a clinical effect that lasts for many years.

MSDF

Have we missed anything? Or is there anything important or interesting to add on the topic?

Dr. Kister

I think your interest was in observational data sets, and I think MS Base registry and others, like NARCOMS registry, they show the power of, kind of all of the people power. It's not the big pharma who is collecting the data, which is very important and has a big role, obviously. It's actual clinicians and actual patients who volunteer their data. And I think patients should be gratified to see that their data is used to actually come up with some insight as to advantage them, come back to the patients and answer some of the questions they had. So I think those databases are very important.

MSDF

I appreciate it. Thank you.

Dr. Kister

Thank you very much.

[transition music]

MSDF

Thank you for listening to Episode Eighty-four of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Carol Cruzan Morton. Msdiscovery.org is part of the nonprofit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is Vice President of Scientific Operations.

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

[outro music]

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

For Multiple Sclerosis Discovery, I'm Dan Keller.

[intro music]

Host – Dan Keller

Hello, and welcome to Episode Eighty-three of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller.

For years, MS researchers have been looking for a measure of MS progression and disability that would be meaningful to clinicians, clinical researchers, patients, and the regulatory agencies that approve new drugs, such as the Food and Drug Administration. To this end, people have looked to composite endpoints that are sensitive to small changes in patient condition and comparable across studies. At the ECTRIMS conference last fall in Barcelona, I met with Dr. Jerry Wolinsky, professor of neurology and director of the MS Research Group at the University of Texas Health Science Center at Houston, who leads us along the path to develop a useful measure incorporating composite endpoints.

Interviewer – Dan Keller

In terms of assessing progression and disability in MS, is there some advantage to having composite endpoints as opposed to the standard tests we’ve looked at?

Interviewee – Jerry Wolinsky

There are several different ways to think about composite endpoints. So one of the things that was introduced almost several decades ago was MSFC functional composite. So this was using three different ways of looking at different components of disability in patients with MS. One was a test of cognition. One was a test of fine motor skills in the upper extremities. And one was a test of walking abilities/walking speed. That particular composite looked very attractive. There was a fair amount of theoretical and practical work behind instituting the composite, and it was used in a number of trials. And it was based on some very important, I think, kind of statistical analysis.

So what it allowed one to do was to take patients either in a given study or across studies and try to normalize the data that you would get from those patients into something called a z-score, which is a way of ranking and evaluating how far across the group of patients people were scattered. And then one could conceptually add up the z-scores and have a composite number, and a single number that you could use to analyze trial data. It seemed to be rather sensitive, and it seemed to work well. But the z-score is very dimensionless, and it makes little sense to the practicing clinician, or certainly to patients, to know that you’re minus-two or minus-five or plus-two, and that maybe this has moved by two-hundredths of a point from the time you started in the study until you got to the end of the study.

So, highly sensitive, seemed very reproducible, maybe even a way to look across studies at different results, but neither patients or physicians and, most importantly, the FDA thought that this would be useful in day-to-day practice. So, while we’ve tested that kind of approach in multiple studies, it just hasn’t worked. But it did set up the notion that we could get a little bit more quantitative in things that could be useful on a daily basis, even using some of the same components of that MSFC.

So instead of thinking about how fast could one person walk compared to another, we said, how fast can a person walk using a timed walk of a fixed distance and at one point in time? And then say how much change over an interval of time would represent something that was likely to be reproducible and, more importantly, likely to be correlated with some measure of quality of life that also was deteriorating?

So then we got to the notion–and this was really best utilized thus far in the trials of 4-aminopyridine in terms of registration studies there–to say could you show a 20% improvement or more in this timed walk over an interval of time? And in that study, a certain number of patients were able to show it, and there was also some correlative data done to show that that amount of improvement correlated with things which were meaningful to the individual. And so I think that helped facilitate getting that drug through the registration process with the FDA.

One of the things that my colleagues and I did in looking at one of the trials in progressive disease, specifically the trial of rituximab in primary progressive MS, where we had the data that goes into the MSFC, because it had been collected in the study, was to try to develop a number of different composites. And actually, when you think about it, the main score that we use to rate studies is the EDSS score, and it itself is a composite. It takes into account graded changes in fine motor skills in what we would call the cerebellar system, in the pyramidal system, in the sensory systems, and cognitive systems. It’s just that the boundaries in moving in these individual functional scales are a little bit more subjective in terms of going from a zero to a one, two, or three. And then the scale itself is rather complicated in terms of how it put together to come to the final score, the extended disability status score. But it’s very well accepted by neurologists, and it’s accepted by the regulatory authorities as the standard.

So we took our standard changes on EDSS, which in this particular study had not shown efficacy across the group as a whole. So we looked at that in the placebo arm, and didn’t contaminate that with the treated arm, to say what was the rate of change on the EDSS alone? But then we also said, what about a 20% change over baseline that had occurred in an individual patient over intervals of testing and not just one that occurred at a particular setting compared to baseline, but one that continued to be seen at the next 3 months and the next 3 months. So it looked like it was a sustained change in the same way that we use EDSS now in trials to talk about sustained or accumulated permanent disability, at least over some interval of time.

So we said, okay, we can construct a progression curve based on that. And then we said, what does that look like? And said, well, this has some dimensions to it that are interesting. And we did the same thing with the Timed 25-Foot Walk, and we didn’t fool around with the PASAT [Paced Auditory Serial Addition Test] the cognitive measure because nobody likes it. Patients don’t appreciate it, and it’s a rather prolonged and not a simple test to use. And this is one that probably could be easily changed out with other cognitive tests that are probably as reliable and easier to complete. And we looked at how did patients progress using that change in the timed walk and said, well, that’s interesting too.

And then we went into the group as a whole and said, okay, how many patients changed on the EDSS over three months, confirmed? How many over six months, confirmed? How many did this on the Timed 25-Foot Walk? Did it cross the 20% threshold? How many did this on the 9-Hole Peg Test and, again, crossing the 20% threshold? And who were these patients, more importantly? So then we could develop series of Venn diagrams–if you will, circles–that showed who did it on just one test, who did it on all tests, who did it on two tests? And looked to see could we get a larger and larger proportion of the population that were showing progression?

And the answer is: We could. And for some tests, the incremental change was small, and for other tests the incremental change was relatively large. But when we looked at the results of the study, then, using different kinds of composites, you fail just on EDSS; you fail on EDSS, or you fail on Timed 25-Foot Walk; you fail on Timed 25-Foot Walk or 9-Hole Peg Test—we don’t care about EDSS in that one—you fail on all three. We could see that we could increase the sensitivity, that is, the number of people who were showing progression, using these kinds of composites, and hoped, therefore, that we could increase the sensitivity to drug effect.

So then we did the next step, which was to take both the placebo arm and the treated arms and say, okay, how did the curves change? So the overall curve showed no statistical benefit with the EDSS, until you went to subgroup analysis. And that was reported in the original paper. But when we modeled this, of course, the overall didn’t show the statistical effect. That’s where we were starting from. When we added in the Timed 25-Foot Walk, it looked like there was a better split. In fact, the effect size for the treatment improved. And this was not across subgroups, but across the entire population.

Interestingly enough, we probably got the biggest punch by throwing out the EDSS and just using the 9-Hole Peg Test and the Timed 25-Foot Walk. That has some advantages, because they can be done by anyone. In fact, they probably could be done remotely, or we probably could convert it to how many steps a day did you take and have your watch feed the message to us over the course of a day. There are a number of interesting different approaches that can be taken to this kind of concept, and some of these are being pursued by a collaborative group spearheaded through the NIH, as well as a private consortium, looking at newer ways to measure progression.

The good news is, I’m sure we’ll find things that are more sensitive. The good news is, I’m sure we’ll find things that are easier to apply. Another part of the good news is that the additional work increasingly is carried out with some representatives from the regulatory authorities to give us a feeling for what they really want to see. And what they would like to see is not just that we have composites that are sensitive and reproducible, but each of those composites that, before using them, has been shown to have some relevance for what patients complain of and what patients are looking for. So that’s the good news.

The bad news is we have to not only develop them, validate them, show that they work, we’ll probably have to constantly be comparing them back, in our future trials, to the standard, until we get our first drug that really works in these new, validated approaches that are being taken.

MSDF

Do you think that different drugs will show you different effects on different parameters within the composite score, or do things pretty much move in synchrony?

Dr. Wolinsky

You know, because multiple sclerosis is such a heterogeneous disease—heterogeneous in many ways, but the simplest one to think about is the lesions don’t exactly form in a way that suits us as trialists. So, many of the lesions are silent for whatever it is we’re trying to test, no matter how carefully we test for them except maybe with really high resolution MRI. So it depends where in the real estate the lesion has hit. So it’s easy to imagine that a relatively small lesion in the cerebellum particularly well-situated could cause some slowing of the ability to do the 9-Hole Peg Test, and yet it might take a very large lesion in the frontal lobe to do the same effect in that system.

In the same way, it may take just a small lesion in a pyramidal pathway, either in the spinal cord or in the internal capsule, to cause a significant change in the 25-Foot Walk and do nothing in the 9-Hole Peg Test. So, conceptually, we want to be able separately test—or relatively separately; the brain is fairly interconnected—separately test as many systems as we can and build upon them. Usually with these composites, you don’t lose too much by adding composites, as long as they’re truly independent of each other. As they become more interdependent, then the more you add, you may lose some of your ability to find small changes statistically. They’ll cancel out.

MSDF

Even though these are composites, you’re still interested in the separate parameters? I mean, it looks like one parameter could offset another, and your composite score could be neutral, even though you have larger changes in the separate parameters.

Dr. Wolinsky

What you’re trying to do, if you’re setting up your composites correctly, is not to have them cancel. And with the z-score we talked about before, it can cancel. With a composite, where you’re expecting each of the scales to be moving in a particular ordinal fashion that is going from better to worse, you don’t care where the worst comes from, if you’re saying we’ll take worse in any system. Where it gets tricky is, once you get good at that, then you might want to say, well, you get two points for getting worse in the walking system, because that’s more correlated with whether or not someone’s employable than it is if it’s in, let’s say, bladder measures, which we don’t have quantitatively—well, we do, but they’re just harder to apply—or perhaps on using other visual pathway measures that have yet to be introduced into the composites very well.

[transition music]

MSDF

Thank you for listening to Episode Eighty-three of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Carol Cruzan Morton. Msdiscovery.org is part of the nonprofit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is Vice President of Scientific Operations.

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

[outro music]

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

For Multiple Sclerosis Discovery, I'm Dan Keller.

[intro music]

Host – Dan Keller

Hello, and welcome to Episode Eight-two of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller.

Depression affects as many as 50 percent of people with MS during their lifetimes. But according to Dr. Adam Kaplin, a psychiatrist in the Johns Hopkins MS Center in Baltimore, it is treatable to a large extent, and with good results. Dr. Kaplin studies the immune basis of depression and cognitive impairment, specifically in MS and central nervous system-related autoimmune diseases. We met in Baltimore.

Interviewer – Dan Keller

Let’s talk about depression in multiple sclerosis. Is it a reaction to someone having a chronic disease, or is there something more going on because of the disease?

Interviewee – Adam Kaplin

It’s a great question, and what I will tell you is one of my patients says to me that you’re either stressed, or you’re dead. We all have stress going on, and it’s always possible to look at something in our life and say, ah, that’s what caused the trouble. But we know now, in multiple sclerosis, the depression is due primarily and dramatically significantly to the inflammation going on in the brain that causes all of the symptoms that you see in MS, such as cognitive impairment, or weakness/numbness/tingling, autonomic nervous system dysfunction; all of those are effects of the MS on the CNS.

And in the case of depression, it is similar. It’s not a character flaw. It’s not a personal weakness. And just to, you know, clarify, one of the best pieces of evidence we have for that is, number 1, that people who are depressed with MS, it does not correlate with their EDSS scores. It doesn’t correlate with their level of disabilities. So if it was you know, gee, it’s just a matter of stress, then those people who are in wheel chairs or on ventilators should be depressed, and those people who are upright and walking around shouldn’t. But in fact, I think the key element is that this is one of the, as they often say, silent symptoms of MS. It occurs to 50% of patients across their lifetime. And it is important you know for people to understand that this is not something that people aren’t rising to the occasion, or those kinds of things.

MSDF

Is depression accompanying MS more prevalent than in the general population, and how serious is it?

Dr. Kaplin

You know people often ask why, as a neuropsychiatrist, why study MS? And I say, you know, why did Willie Sutton rob banks? That’s where the money is. MS has the highest rate of clinical depression of any medical neurological or surgical disease. Again, 50% of people, following the diagnosis of MS, will have a clinical depression. We can talk about what that is. And it turns out that that’s in any clinic you go into – neurology clinic – that’s one in four patients. If you go out to the waiting room, one in four patients will be suffering from a clinical depression.

MSDF

How serious a problem is it? What aspects of life does it affect? Does it affect everything, and how serious is it?

Dr. Kaplin

I think what is often misunderstood about the depression in MS is, I would argue, that it has the highest morbidity and mortality of any of the symptoms of MS, in the sense that it is the third leading cause of death in the largest study that looked at, across the lifespan, what causes death in people with MS, [found] a study out of Canada, where it’s more prevalent because of the higher elevation and the lower vitamin D levels, probably. And it is absolutely the case that seven-and-a-half times the rate – the suicide rate in MS – to the general population. And in fact, in the studies that were done, 30% of people with multiple sclerosis will have thoughts of suicide at some point during their life. Ten percent – fully 10% will attempt suicide. And that lethality is profound.

But if it doesn’t kill you, it is important to understand that it has significant, significant morbidity associated with it. Just to begin with, the number one correlate of quality of life of patients—more important than their pain, or more important than their cognitive impairment, or weakness, or other symptoms—the number one correlate of the quality of life of the patient is their depression or whether they are depressed or not. And it’s similarly the number one quality of life of the care givers—not whether they have to push them around in a wheelchair, it is whether their loved one is suffering from a clinical depression. So it has significant morbidity and mortality associated with it.

MSDF

Are there aspects of serious depression in MS that are very characteristic? Any different from other severe depression? Or can it be recognized in the same way with the same diagnostic criteria?

Dr. Kaplin

There actually are some specifics to MS, although that hasn’t been well-published. I can be clear about things that are well-supported by the literature, and then those that are my clinical experiences. What I can tell you is that the way we diagnose depression in MS is the same way we diagnose depression in people without MS, which is you have to have 5 of 9 symptoms greater than two weeks, one of which must be either decreased mood or decreased interest. And we remember it by SIG-EM-CAPS, the nine symptoms. Trouble with sleep, where people are often having early morning awakenings or hypersomnia where they just sleep all day. Loss of interest, people’s get up and go has gotten up and gone. Feelings of guilt or worthlessness – and that’s a big problem, because patients who are depressed as a result of that often won’t seek help. You have to ask about it. They won’t volunteer it. And loss of energy or fatigue; low mood – that’s the sadness part; concentration problem; appetite changes, either increased or decreased weight; and psychomotor retardation, they’re not their normal bubbly self; and thoughts of death or suicide.

With MS, what I will tell you, I find that patients with MS often, rather than sadness, have very frequently irritability. That tends to be more common. And sleep is usually decreased, not increased, so I see very frequently increased early morning awakening and those kinds of things. One pearl, though, to keep in mind is – or two pearls – if you’re trying to make the diagnosis of depression in somebody with MS, the first thing to do, because there are overlapped symptoms like fatigue, like concentration problems between depression and MS, so there is frequently, in up to 80% of people, will have diurnal variations in their moods; so usually worst in the morning and better at night. Sometimes it’s reversed, but you know that person has the same life circumstance, the same disease circumstance in the evening that they did in the morning, but their mood has changed dramatically, often, with MS with these cyclical changes. And that’s a good indication that it’s not demoralization; it’s depression.

The other thing is ask the loved one. Get an outside informant, because nobody gets the brunt of it quite like the family. And they know that person, and if the family member says the one thing I hear so often, this is not the person I married, then you’re pretty much on the right track if you’re thinking about depression.

MSDF

How amenable to treatment is depression in MS?

Dr. Kaplin

I think that that is probably one of the key aspects is to understand that it is very treatable. So my expectation when patients come to me and I diagnose them with depression is that I will get them a hundred percent well with respect to those SIG-EM-CAPS symptoms, back to their baseline. And it’s very hard to get patients a hundred percent well from their gait problems; a hundred percent well from their cognitive problems. And, again, what I tell people is, look, I can’t tell you whether your cognitive impairment is due to the depression or due to the MS, or maybe it’s 10% depression/90% MS or 90% depression/10% MS. But I can promise you this: treating the depression, the depression is much more amenable to treatment. We don’t have good treatments for cognitive impairment in MS to reverse the cognitive impairment, but boy, we can reverse it if it’s a symptom of depression. What’s really exciting now is that we are now understanding more and more that many of the treatments you use for depression end up being good nerve tonics.

So, there was a double-blind placebo-controlled study of fluoxetine demonstrating that, in patients who weren’t depressed with MS, they had fewer gadolinium-enhancing lesions over 24 weeks. And then there was the FLAME study in a related kind of way looking at fluoxetine as a way of significantly enhancing the recovery of hemiplegic stroke patients. So it turns out that I wasn’t so misguided in thinking that studying the immune basis of depression would be important, because as it turns out, our treatments actually do have an effect on the nervous system and the immune system for general types of depression as well.

MSDF

That sort of covers the SSRI class. What about tricyclic antidepressants? What about SNRIs? Do those fit in?

Dr. Kaplin

Yes, so absolutely. So the topic of how to choose and select the right treatment for patients with MS is … we could spend an hour and just sort of get only the highlights done there. But generally there’re sort of two strategies. One is to use a medication that has the fewest side effects, so that you won’t have drug-drug interactions with the patient if they’re on a numerous medicines for other concerns—their other symptoms and syndromes—that the antidepressant won’t interfere with it. And so along those lines, escitalopram and sertraline have the fewest drug-drug interactions. You essentially don’t need to look up drug-drug interactions if your patient is on one of those two medicines.

The other approach is to say let’s choose a medicine that will have favorability with respect to the side effects, will be beneficial for the problems that the patient has. So a classic example is duloxetine is FDA-approved, not just for depression, not just for anxiety, but also for neuropathic and musculoskeletal pain. So here you’re talking about one treatment that will help you with the fact that your patient, their depression will get better; their neuropathic pain will get better if they have migraines—which are often a comorbidity—that will also benefit the neuropathic pain from that as well. And you know you will get two birds with one stone, as it were.

And then the tricyclics, as you had asked about, we’ve had a lot of experience with them. They also will benefit in terms of the urinary incontinence problem. They are strongly anticholinergic, and so you can also benefit in terms of preventing the urinary/bowel problems. So really Cymbalta as just sort of son-of-tricyclics, has some fewer side effects, but doesn’t, therefore, cover some of the things that the tricyclics will.

MSDF

As you alluded to earlier, the depression in MS may largely be a result of immune processes going on—inflammation, cytokines, things like that. So how well do the disease-modifying therapies of MS attack the depression?

Dr. Kaplin

You know you mentioned cytokines. So that is another way that we know that this is due to the inflammation—the depression in MS—and not just other things, because for instance, interferon-alpha used to treat patients with hepatitis C will cause depression in upwards of 20 to 25% of people who take it, not when they first start it, but within you know a week to two weeks after starting it, you know, then up to eight weeks. So that’s just one cytokine, and in MS, all of the cytokines get activated. And similarly, interferon-beta that’s used, or Copaxone, you know, the ABCR drugs that we’ve used to try to—you know, with great effect since 1993—to slow the exacerbations down in MS; they don’t stop the inflammation, they just alter it. And so not surprisingly, they do not have antidepressant properties.

But when you look at something like Tysabri, we actually have not published this yet. We did present it at a MS conference but working in collaboration with Biogen. We are going to publish shortly data that shows that, in a double-blind placebo-controlled study of adding natalizumab to Avonex, or adding placebo to Avonex, those patients who were depressed to begin with show a dramatic and statistically significantly decrease in their depression as a result of the natalizumab. So natalizumab is actually quite a good antidepressant—we have data for it—because that really does shut the inflammation down in the brain, and since that’s causing the depression in MS, that’s what benefits them.

MSDF

Just to clarify, natalizumab is a good antidepressant in MS.

Dr. Kaplin

Exactly right. That’s exactly right. Although, you know, it’s good that you clarified that. What’s interesting is that now that people are beginning to appreciate the role of the immune system in idiopathic depression, people are beginning to say, hmm, maybe we should be looking at these anti-inflammatories and seeing if the anti-inflammatories benefit patients with depression. Now, nobody has tried natalizumab, but TNF-alpha inhibitors have actually been tried. There was a study out of Emory looking at using TNF-alpha inhibitors for refractory depression. And I think coming down the road there will be more and more studies that begin to show the role of anti-inflammatories for not all, but some people with refractory depression.

MSDF

Yes, I’ve seen some studies on anti-inflammatories—traditional ones, NSAIDS sort of things—presented a German study at a neurology conference. Didn’t do too much.

Dr. Kaplin

Yes. What I can tell you is that not all NSAIDs are created equal. Celecoxib actually now has five studies that are placebo-controlled that have shown its benefit for depression or bipolar disorder. And so when added to antidepressant by itself: No. But when added to fluoxetine or—I can’t remember what other; it might have been sertraline—it clearly had a statistically significant improvement in the depression response, celecoxib. But not all NSAIDs are created the same.

MSDF

What about non-drug therapies, cognitive behavioral therapy, even just physical activity? And, if someone’s depressed, isn’t it hard to get them up and do physical activity?

Dr. Kaplin

Well, I’m so glad brought that up, because I’d be remiss to forget that. So all of the data says, look, therapies like cognitive behavioral therapy are effective for mild and moderate depression. Antidepressants are effective as well. The data shows that the antidepressants work quicker, but that the combination of antidepressants and psychotherapy is much better than either one alone. So that’s a crucial issue. And to make sense of what has happened—and often when people are depressed, they’ve been depressed, and that’s caused damage to their professional life and personal life, and having someone help them sort of, depending how long the depression’s been going on, sort of talk them through, coach them through, how to get back up and going.

However, in severe depression, you can talk till the cows come home. If your patient is so depressed that basically they have this tunnel vision, and all of the options that are in front of them, the kind of mental flexibility that you need for CBT to work, for instance, it will not work if you patient is really severely depressed. You have to get them started with the antidepressant, which really then serves as a catalyst for the psychotherapy to kick in. And then the aspect of exercise, you can’t really pick a topic related to MS where the answer isn’t exercise. Cognitive impairment, absolutely exercise is beneficial.

Depression, exercise is beneficial. It stimulates growth hormones that have positive neurological effects on the CNS, as well as on the peripheral nervous system and body.

What I tell people, again, is that if your patient is severely depressed, they’re not going just go back out and start running. So you’ve got to begin to have a plan where you say, look, we’re going to begin this medicine. As you start to be able to have the ability to you know maybe push yourself more than you might usually and just sort of walk down the block, and then you know walk for a mile and then start jogging for a mile and sort of build up to it, that’s very beneficial.

MSDF

Are there barriers to recognizing and/or treating depression both on the patient’s side and on the physician’s side?

Dr. Kaplin

The big barrier on the physician’s side is, you know, don’t ask, don’t tell. So if you don’t think of depression, or worse, if the neurologist says, well, I went into neurology not psychiatry, you know, this whole depression thing, that’s not my bailiwick, that’s not my responsibility, you’re missing the fact that this is —first of all, this is very rewarding. There’s nothing else that you could treat that gets a patient from being non-functional, sitting at home, not taking care of the family, not working, in a bed to fully functional, taking care of the family, back at work, like treating the depression can. But also it is. It affects all aspects. It affects the patient’s compliance with all your other medicines. It affects their ability to exercise, etc., etc. So, you know, you’ve got to think of it.

And then you have to know something about treating it. One of the big problems with neurologists when they treat depression is that they don’t appreciate the fact that the goal is to get that patient a hundred percent well, because you sort of have this sigma curve where, if you get them 50% well, they’re still in that sort of steep portion of the curve where something comes along—an MS attack or you even a viral infection—and they will slip right down that curve. Whereas, if you can push them way out into the hundred percent well, that’s great. Now you can’t always do it with one medicine. You take the dose as high as the patient can tolerate, where the side effects don’t become worse than the depression you’re trying to treat. But then you might need to add another medicine, an augmenting agent or something, so you’ve got to make sure you recognize it and treat it.

And then, what I always tell my colleagues—and my colleagues at Hopkins are wonderful; they do appreciate you know you’re treating the whole patient, not just you know their reflex arcs and that kind of stuff—and what they are very good at is, if the patient is depressed and suicidal, that is the psychiatric equivalent of a heart attack. So then they will get in touch with me and we’ll work together. So if you’ve got someone who’s suicidal, you really want to get in touch. Unless you have the utmost experience and confidence in treating the worst cases of depression, you probably want to get a psychiatrist involved, or mental health professional involved, to help coordinate the care for someone like them.

MSDF

Very good! I appreciate it.

[transition music]

MSDF

Thank you for listening to Episode Eighty-two of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Carol Cruzan Morton. Msdiscovery.org is part of the nonprofit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is Vice President of Scientific Operations.

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

[outro music]

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

For Multiple Sclerosis Discovery, I'm Dan Keller.

[intro music]

Host – Dan Keller

Hello, and welcome to Episode Eighty-one of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller.

The science of pharmacogenomics can help identify those genetic variants that are associated with a high or low risk for experiencing an adverse drug reaction or a beneficial therapeutic response. While at the ECTRIMS conference in Barcelona last fall, I spoke with Kaarina Kowalec, a postdoctoral fellow in the Pharmacoepidemiology in MS research group at the University of British Columbia in Vancouver, Canada. We discussed the potential for using pharmacogenomics to optimize the risk/benefit profile in a patient's favor, focusing first on the risk of liver injury with interferon-beta.

Interviewer – Dan Keller

How are you using pharmacogenomics to assess the risk for interferon-beta-induced liver injury?

Interviewee – Kaarina Kowalec

Yes, essentially we have two groups of patients. We have ones that have had the drug reaction and then the other ones that have been exposed to the same drug, but do not have the drug reaction. And so we take a saliva sample from all of them, and then we’re basically looking for genetic markers that would either increase or decrease the risk of having the drug reaction. And so by recruiting all these patients, we can use their saliva or their DNA to study whether or not they have some kind of genetic variant or genetic marker that would protect them from having the drug reaction.

MSDF

Are you doing genome-wide association studies or looking for specific markers?

Dr. Kowalec

Yes, we’re doing two-fold actually. So the first one is a candidate gene study. So this is looking at a more targeted approach to looking for genes that, based on previous literature, would be likely to be involved in the mechanism of predisposing to liver injury from interferon. So either this is related to interferon the way that it’s degraded in the body, the response towards interferon is regulated, or it can be related to the liver toxicity side. So there’s a lot of other studies that have been done looking at the genetic basis of liver toxicity from, say, flucloxacillin, amoxicillin clavulanates, a few other thrombin inhibitors, and some other cancer therapies. And so from that information we can look at those genes in our cohort. So that’s sort of the targeted approach.

And then secondly, we’re doing more of a hypothesis-free type of approach, which is a general genome-wide association study. So this is where you look at every gene in the human genome, so over 20,000 genes. In each gene, you would look at, say, a few different markers within each gene. So we have a total of 1.7 million different markers that we’re looking at to see if they modify the risk of experiencing liver toxicity.

MSDF

Are you also doing the basic investigation, essentially heat maps, to see what genes are induced or suppressed when interferon is given?

Dr. Kowalec

No, so that would be, I guess, more microarray or gene expression. I think that would be sort of the next stage. If we could isolate one gene that would be involved, then we could I think then look at the expression of the gene, because, of course, that would be also important to see if interferon has any direct effect on turning on or turning off or reducing or increasing the level of a certain gene. But that would be probably for the next project, I think.

MSDF

Are you trying to develop a risk assessment model?

Dr. Kowalec

Yes, so essentially kind of like a test. So it would be once a new patient would come into clinic and, say, they were going to start one of the interferons, we could take their clinical and demographic information, like whether or not they were female, whether or not they were within a certain age group, whether or not they drinked, whether or not they took different concomitant medications; and then, as well, take a spit sample from them. And then, hopefully, within a few hours or a day or so we could tell them whether or not they would fit into a low risk or a high risk of having the drug reactions. So then the clinical decision by the neurologist or the nurses could then decide what medications they should go on. Of course, if they were in the low risk category, put them on that drug. And then if they were in the high risk, then maybe suggest something else, or still go on the medication and maybe just have more blood work done to monitor them a little more closely.

MSDF

Where does this stand? Developing a model is a long process. Has it started yet?

Dr. Kowalec

We’re in the discovery phase, so I’m going to be presenting the discovery phase where we’re initially trying to find the markers. And so we’ll finish this up within the next few months, and then the validation phase, which is basically where we would want to replicate these findings in an independent international cohort. So we have another cohort of patients that are from the US, as from Europe. That will probably take about a year or so. And then from there you could maybe implement it into the clinic, but likely the goal with looking at interferon-induced liver injury might be that we would use this information to study drug reaction with the newer medications. Because the new oral medications come into being used more, interferon might be used less, and so this just might provide some pilot work, I guess, for some of the newer oral medications.

MSDF

Will all this focus always on liver, or are there other toxicities that you would look at?

Dr. Kowalec

There’s definitely quite a few areas that I would want to look at. One, of course, is probably in the mind of most clinicians and patients as well would be PML or progressive multifocal leukoencephalopathy with natalizumab and then also with some of the newer medications as well. That would be probably the one, you know, stands out in most people’s mind that would be the likely area to study to see if we can reduce the incidence of that type of more severe drug reaction for sure. Some of the new medications definitely suppress the levels of white blood cells quite a bit, but that still kind of also ties in with PML. Mitoxantrone is not used quite as much, but it’s got a limited amount of use, because it’s associated with not only leukemia but also with inducing heart toxicity. That’s another area that would be frightening, obviously, for a lot of people. But I think those would be sort of how you could kind of round out what areas would be next likely drug reactions that would be needed to be studied.

MSDF

Do these kinds of investigations require networks of collaborating centers or databases?

Dr. Kowalec

One center definitely can’t do it all. In order to get the number of cases that you need of the drug reaction, you probably get maybe 5 to 10 per center, and so you probably need somewhere in the range of 60 to 100. And so what we did was, because of the really strong network that we have in Canada of the Canadian MS Clinics, we use that, as well as we capitalized on another drug reaction surveillance network called the Canadian Pharmacogenomics Network for Drug Safety. Using those two different networks, we were able to recruit enough patients to form our discovery cohort. And then for the replication cohort, we used some of our connections in the US and then abroad. But definitely it’s a multicenter type of study, for sure.

MSDF

Can these sorts of models be used also for predicting who will respond best to a drug, not only worst? Some drugs are taken from the market, because you get adverse reactions, but they work for some people who don’t have adverse reactions, and that’s a loss.

Dr. Kowalec

Yes, it’s definitely unfortunate, and even in the case of natalizumab, where it was taken off market because of PML, there were obviously patients who were so passionate about having this drug available to them that they were able to get that decision reversed and just released on a more stringent, I guess, criteria. I’ve never heard of a drug being put back on the market because of pharmacogenetic findings or because someone was able to find a marker that would prevent people from having a drug reaction. I think that, for example, the FDA or Health Canada or any of the European agencies I don’t believe that they would feel comfortable enough with letting a drug back out there knowing that, even if they found some kind of genetic marker.

Two drugs, ximelagatran (7:17) and one other cancer therapy, they were taken off the market because of liver toxicity concerns. And what’s interesting is that it was about a similar incidence as what interferon-beta-induced liver injury was. But, of course, with MS there wasn’t many medications, so that’s probably why interferon was probably allowed to stay on the market. But those drugs were taken off the market, and then they found some genetic markers, but they weren’t quite as strong, I guess, as they were hoping. And so it was not going to work as a predictive risk model or as a predictive genetic test, so they weren’t going to be allowed back on the market.

But I think the ideal time to look at these types of genetic markers would be probably in some of the final stages of, say, clinical trial testing. And maybe pharmaceutical companies might be doing this, I’m not sure, but to look at these types of genetic markers in those stages would be really beneficial, because if you see them as they’re developing them, you could offer them as kind of like a companion diagnostic type of test, so whenever they would release the drug. Usually these drug reactions don’t actually occur until you’ve treated probably ten to fifteen thousand people, so that’s the other difficulty. So maybe another stage would be to just do sort of like an active surveillance to sort of recruit patients as they’re on the drug and just monitor all of them. But, of course, that takes a lot of money and takes a lot of time, so you need the funding for that type of study.

MSDF

This would be like a Phase 4 post-marketing study.

Dr. Kowalec

Yes, exactly. And they do that, right. They do a lot of active surveillance for drug reactions whenever a new drug comes onto market. But to actually develop some kind of predictive biomarker test at the same time, is not really done pretty readily, at least to my knowledge. So it would be great, because if you see how much money goes into developing every drug, you know, and if we want to keep it on the market, then maybe that’s what you have to do.

MSDF

People are developing in vitro liver assays. I guess that’s an early stage sort of thing before they go through a whole development process.

Dr. Kowalec

Yes, exactly. And that will definitely help as our technology certainly gets a lot better in the future, and we can study the liver much more readily, especially in people with MS. Just studying MS as a disease on its own is really difficult, and so studying the liver is very low down the list. And so we don’t even know really if MS affects the liver on its own, so that could be another entire study.

MSDF

Anything important to add?

Dr. Kowalec

You know, I really hope that we eventually get to a day where patients can take a drug that’s really effective. We’re definitely getting there. We’re definitely getting drugs that are more effective, but at the caveat that they definitely are more toxic. That’s definitely unfortunate, because the patients are scared, right? These side effects are fatal sometimes and are really very worrisome.

And I can give one anecdotal experience that I had with a patient that experienced liver injury from interferon. And I’ve certainly had a lot of people that didn’t really believe that this drug reaction was all that important sometimes to study. And I met this one patient that experienced it, and she said, you know, I’m not really worried about this drug reaction itself. It’s just I don’t know what has happened to my liver. I know this one instance is over, but now for the rest of my life, I’m scared of every drink that I have or every time I want to take an acetaminophen pill for a headache or a fever or whatnot. If they don’t have to worry about one additional thing, you know, they’re already worried about how MS is going to affect their life. If we can maybe eliminate something like this, it’ll help some patients.

MSDF

Very good, thank you.

Dr. Kowalec

Thank you.

[transition music]

MSDF

Thank you for listening to Episode Eighty-one of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Carol Cruzan Morton. Msdiscovery.org is part of the nonprofit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is Vice President of Scientific Operations.

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

[outro music]

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

For Multiple Sclerosis Discovery, I'm Dan Keller.

Full transcript:

[intro music]

Host – Dan Keller

Hello, and welcome to Episode Eighty of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller.

Interferon beta is a well-known and long used treatment for relapsing-remitting MS, but it's not without potential problems for some patients. While at the ECTRIMS conference in Barcelona last fall, I spoke with Kaarina Kowalec, a post-doctoral fellow in the Division of Neurology at the University of British Columbia in Vancouver, Canada. We discussed interferon beta and other drugs and their potential for liver toxicity.

Interviewer – Dan Keller

In terms of liver toxicity of interferon beta, what's the problem?

Interviewee – Kaarina Kowalec

I would say that about 1 in 50 patients that are exposed to this drug will experience a side effect known as drug-induced liver injury, or liver toxicity, essentially; it's an abnormality in their blood work. Most times it'll just go back down to normal and everything is fine, but in the rare occurrence sometimes it can lead to more severe outcomes such as needing a liver transplant, sometimes even liver failure, and sometimes even death. That's definitely a very rare scenario, but it certainly is an issue, and it's definitely a worry for some patients and definitely for clinicians, as well.

MSDF

Also, it's not only interferon, a lot of drugs have liver effects. Is that right, new drugs especially?

Dr. Kowalec

It's the number one reason that drugs are taken off the market, and it's usually one of the top concerns for any new drug that's entering into the market. Obviously, the liver has many different functions, but one being that it detoxify foreign components like drugs like interferon, like alcohol, food, many different things. So it definitely plays a major role, that's why it's usually effected so much.

MSDF

What are some of the factors that affect both efficacy and toxicity of drugs in general?

Dr. Kowalec

You know, if you see it kind of a pie chart, the genetic component can be pretty variable. So from person to person, it could be anywhere from a few percent to up to 50 to 60%. But the rest of that pie, I guess, is made up of variation in how much of an enzyme we make that needs to detoxify the drug, as well as our age, our BMI—how much we weigh—how tall we are, whether or not we're male or female. There's a variety of different demographic-type factors that come into play, as well. It's definitely very difficult to predict who will have a safe and effective response to a drug.

MSDF

Does polypharmacy play a role, especially you had mentioned enzymes; things that induce or suppress enzymes?

Dr. Kowalec

Yeah, definitely. So in the case of an interferon, there's some evidence to suggest that interferon might suppress some of the cytochrome, or drug-metabolizing enzymes. And in that case if they were taking any additional medications, such as like Tylenol (acetaminophen) or ibuprofen, that could create an issue because interferon is inhibiting the enzymes that are necessary to detoxify the acetaminophen, then obviously the body might have trouble with just acetaminophen on its own.

MSDF

All interferon betas, do they vary in their effects?

Dr. Kowalec

Yes. The versions that people with MS get as a drug therapy, there is a few different variations. So I guess half of them are made in a Chinese hamster ovary cell line, and then the other half are made in an E. coli cell line. So there are differences in the immunogenicity of those two forms, so the ones that are made in the animal cell lines are more similar to the version that we would all make endogenously, whereas the versions that are made in the E. coli cell lines are different, they're slightly more immunogenic. They're just more foreign than what we would normally make.

MSDF

Is it a difference in amino acid sequence, or glycosylation, or both?

Dr. Kowalec

Yeah, exactly. So the amino acid sequence is slightly different for the E. coli cell line versions, as well as the E. coli version is not glycosylated. So, again, that's why it's a little bit different than the human version.

MSDF

Do you know some of the mechanisms by which interferon betas cause liver injury?

Dr. Kowalec

So how it causes liver injury exactly is certainly unknown, and that's definitely an area of which I'm trying to figure out. There's two sort of competing theories, I guess. One is that interferon, because we make it endogenously, but this version is obviously still different than the version we make, it might be that obviously in MS they have an aberrant immune system; they could be recognizing the interferon as being a foreign agent and its attacking it, and then some of the cytokines that are released might be targeting the liver. So that's one theory. The other theory is that once interferon is incorporated into the cell, it might have some sort of direct effect on the mitochondria, and so it might be that it's reducing the energy metabolism of the cell and causing harm into the liver. But which of those two, we're not sure yet.

MSDF

Do you know risk factors for liver injury, and as they are picked up by aminotransferase elevations?

Dr. Kowalec

Yes. And some of the risk factors that we know for interferon-induced liver injury are related to gender, age. Sometimes it's polypharmacy, so whether or not they're taking acetaminophen or ibuprofen. One study will come out that'll say that there is an effect, one study comes out there's no effect, so it's still a little bit unclear. With gender, we know that for males they are more likely to have some of the more minor transient elevations in the aminotransferases, whereas females are more likely to be at risk for the more severe symptomatic hepatitis, or liver injury, I guess.

MSDF

And is it equally prevalent, or there's different gender prevalences?

Dr. Kowalec

I would say that overall when we looked at all the genders together, it was about the same, about 1 in 50, or 2% or so. I would say that if you're looking at just severe injury, the effect that's more symptomatic, something that a patient would actually notice, it's likely that females are more susceptible.

MSDF

What about duration of treatment, does that have an effect; early, late, how long?

Dr. Kowalec

Yeah, typically it's quite quick that they would experience this. So the median time is about the first 3 months is the greatest risk period—I guess probably 3 to 6 months – but it certainly can still occur later on, say even 2 to 5 years, or even 7 years later on, so that's why it's still really necessary to remain diligent on testing their liver aminotransferase levels even later on, even like I said, 5 to 7 years after being on treatment. The effect doesn't seem to go away, for some people anyways.

MSDF

I suppose while you're taking it you're getting older, and also you probably have different medications coming in and out.

Dr. Kowalec

Yeah, and it's not even just the other pharmaceutical therapies that you're taking, it could also be your diet, how much you exercise. There's a lot of things that can affect the liver aminotransferases, unfortunately, so sometimes it can be difficult to determine whether or not it's actually interferon beta that's the causative agent.

MSDF

What should patients be looking for?

Dr. Kowalec

You know, I think just staying up with a healthy lifestyle; not drinking excessively, eating the right foods, making sure that whatever therapies that you are taking are compatible with interferon. Your neurologist or your clinician will advise you on those areas anyways, and also keeping an open dialog with your neurologist in that you know exactly what the risks are with taking any medication. And most times your clinician will be able to tell you everything that'll be possible side effects, so just keeping an open dialog with the clinicians, I think, is great.

MSDF

Are there symptoms which might raise concern?

Dr. Kowalec

You know, I mean sort of the typical things that we think of with liver issues, like jaundice, abdominal pain—they're really like, I mean, abdominal pain that can be a symptom from many different things, right? Malaise, same thing. Really I would say jaundice is probably one of the things that would stick out in my mind to most people as having an issue with your liver, right? By the time you notice symptoms, it certainly is in the more severe end, so usually you have something else that would precede that, like the abnormal blood work. So most people don't get to that stage, which is good.

MSDF

Is there something physicians should be doing or looking out for?

Dr. Kowalec

No, I would say they're doing a really great job with just monitoring the blood work. They know that once typically patients get to 5 times the upper limit of normal for ALT, or the liver aminotransferase, that's when it's recommended that they stop the drug. So normally because they are tested quite often for the blood work abnormalities, the clinicians are really going to go about monitoring by lowering the dose of the drug or just stopping them, and then slowly titrating them back on again. They still have many options if they experience the side effects, so they're doing a great job with monitoring.

MSDF

Is this becoming less of a problem with new drugs, vis-à-vis, interferon beta itself?

Dr. Kowalec

I believe almost all of the new oral medications have all had some case reports of having liver injury associated with them, which is unfortunate. But, again, like I said, most drugs will use the liver in order to be detoxified, it's not, I guess, surprising that this is happening. So I think that we definitely need to study the theory. And that's sort of why we're studying interferon beta, because there's so many people that have taken it, there's enough people that we can study, whereas the new medications, they haven't reached sort of that level yet; they don't have 20 years of data yet. So that's why interferon beta really represents a really great way to study this type of side effect, because now hopefully maybe some of these findings we can apply to the new medications that are going to be more relevant in the future.

MSDF

Have you been able to see whether a history of interferon beta affects susceptibility to liver injury with any of the newer drugs?

Dr. Kowalec

I've seen a few patients that have had liver toxicity from interferon, and then gone on to take, say, glatiramer, and they have had that same reaction, or Copaxone. Individual clinic, they've seen it, but they just haven't had many publications on that, so it's sort of unclear, I guess, right now. I guess I should still say in the wider literature in other liver toxicity from, say, like antibiotics, there are some common mechanisms. It seems like that some people, that if they have it to one drug, they have it to multiple drugs. So there could be some underlying, I guess, common mechanisms between all of them.

MSDF

It would be hard to separate out whether it's a function of the patient being susceptible liver to liver injury from almost anything, versus having a history specifically of beta-interferon.

Dr. Kowalec

Yeah, we don't know the long-term effects of interferon beta, we don't know really what happens to them in the long run. We can only really follow the ones that have had the really severe outcomes, like liver transplant, for example. But people that experience the more minor elevations, or even the level that we study, most often we see that the liver enzymes go back down to normal. But, you know, we're only looking at this for maybe 5 to 7 years, and then after that we don't know what happens. And then, of course, then once they get older, you would expect that things might go downhill and they might have more issues.

MSDF

Have we missed anything important?

Dr. Kowalec

This is an area that with respect to toxicity with the MS medications, it's definitely an area that is not as well studied, because, of course, the overall goal is to have an effective treatment. If we have an effective and safe treatment, that's the end goal, but that's not always what happens, because we can't sort of have everything that we really need. And so I think studying these areas is definitely really important, because although patients want their disability to be prevented, they're willing to take a lot of risk. And they shouldn't have to, they should be able to have an effective treatment that is safe, as well. So I think by studying these adverse drug reactions more often, I think we'll hopefully get to that end goal eventually.

MSDF

Very good, thank you.

[transition music]

Thank you for listening to Episode Eighty of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Carol Cruzan Morton. Msdiscovery.org is part of the nonprofit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is Vice President of Scientific Operations.

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

[outro music]

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

For Multiple Sclerosis Discovery, I'm Dan Keller.

[intro music]

Host – Dan Keller

Hello, and welcome to Episode Seventy-nine of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller.

Wouldn't it be great to be able to predict who will develop MS? Then those people could be followed prospectively, possibly medication could eventually avert the disease, and at least some medical planning could be done early. Immunologist Dr. Nancy Monson, an associate professor in the department of neurology and neurotherapeutics at the University of Texas Southwestern Medical Center in Dallas, has developed a promising diagnostic test for relapsing-remitting MS that looks at unique antibody gene mutation signatures in B cells in cerebrospinal fluid.

Interviewee – Nancy Monson

We can identify with 86-92% accuracy patients who either have MS or will develop MS in the future.

Interviewer – Dan Keller

How long is the future?

Dr. Monson

So the longest patient we've tracked so far is 17 months out.

MSDF

And how quickly might this turn into MS?

Dr. Monson

As soon as immediate. It kind of depends on, you know, what the patient's history has been really in that respect.

MSDF

This is tested so far on a pretty small cohort, is that right?

Dr. Monson

No, we tested it on three different smaller cohorts here at UT Southwestern. And then when DioGenix licensed the IP on MS PreCISe, they actually took it to clinical trials, and we're writing that workup now. And that was 300 patients in that trial.

MSDF

It looks like there's very good sensitivity, but what's the specificity in terms of other kinds of neurological diseases, inflammatory diseases, anything else?

Dr. Monson

Right. So we're just starting to figure that out. So the accuracy is based on comparing true patients who convert or evolve to MS versus patients who do not. That's where the accuracy mathematics comes from. But in that respect, the control patients that we've looked at so far, the majority of them have very low scores to no score detectable at all in those patients. But some of them do have higher scores. And we don't understand that yet, because we don't really understand any CNS disease for that matter and how the immune system is operating in there. But we're working on trying to expand the control cohorts that we can really kind of nail down, you know, which ones they'll be different from and which ones they won't be different from.

MSDF

Is it worth doing healthy controls also?

Dr. Monson

Not really. Healthy controls are always really low, and so I don't think that's a very fair comparer because it's just not very stringent, right? It's not very hard to be able to figure out who are the healthy donors with MS PreCISe. But when you start looking at people that mimic MS, like people with sarcoidosis and people with neuromyelitis optica, you know, then, you start to really have a rigorous ability to test MS PreCISe. And it's quite possible, when we start expanding those kind of control cohorts, the mimics of MS, that the MS PreCISe scoring mechanism will have to be adjusted to kind of push those different control groups away from the MS group and distinguish the two better.

MSDF

When we talk about these gene mutation signatures, what are you really looking at? Or for?

Dr. Monson

So if you think about B cells in the blood, they produce antibodies, which are designed to survey the entire body for infection. Okay? So the way that they do that is to have a really great ability to bind to infectious agents or foreign agents in your body. So the mechanism that a B cell uses to do that is called somatic hypermutation or affinity maturation. And what that means is just fancy immunology speak for saying that they incorporate mutations into their antibody genes in order to bind to their targets better, okay? So it makes them more effective in being able to find them and to stick to them.

So we've done an initial look at the different antibody genes that were being used by MS patients versus our control cohorts, and didn't really see that the genes themselves were that different that they were using. So then we thought, well, maybe it's the somatic hypermutations that they're putting into those genes that are really different from what we see in the controls, and that's what turned out to be true. So it turns out that there is a family of antibody genes that incorporate these somatic hypermutations allowing them to bind to their target better that we don't see in healthy people or people with other neurological diseases. In fact, in some cases some of these codons will accumulate mutations up to seven times more than what we see in control cohorts. And that's what MS PreCISe is based on, is the accumulation of those mutations into those six codons. So the more mutations there are in those six codons, the higher the MS PreCISe score you get, and the more likely it is that you actually have MS.

MSDF

Are you essentially losing tolerance here, because of the hypermutation there's more chance that you're going to start to recognize self-antigens?

Dr. Monson

So we have actually taken the antibodies that have these somatic hypermutations in those six codons and looked to see if they bind to human brain tissue. And it turns out that they absolutely do, hands down. We've tested 38 of those so far, and 90% of them bind to neurons in the brain. So we know they bind to self-antigens, right? But that doesn't necessarily mean that they've lost tolerance or that they're proinflammatory, for example. It's possible that the B cells that are making these antibodies are actually somehow able to quiet the immune system. We don't know yet because we haven't been able to do those experiments to see. But obviously, when you see a lot of B cells that are reactive to the brain, right, that they're antibodies are reacted to the brain, that is an alarm to us that they have probably overstepped their boundaries, have not gone to school correctly and done what they're supposed to do. But we still have some experiments to do to make sure that that's what's going on with it.

MSDF

I suppose that leads to a question of, are they pathogenic in themselves? Or are they bystanders or regulatory somehow else?

Dr. Monson

Right. That's a really good question, and we don't know the answer to that. There're some experiments we can do to start testing that, but it's very tricky to do those experiments, particularly in the mouse models we have right now. We're not going to give these antibodies to people and see if they get MS, right? So you have to do all that testing in animals or in vitro. And because no one prior to this time has ever actually been able to demonstrate that antibodies from B cells of any type in MS patients actually bind to brain tissue, I mean, this is completely undiscovered country. We're kind of out there on our own trying to figure out how to best ask those questions, and it's a little bit tricky. But I'm fortunate to have a lot of really brilliant people that work with me, and so we'll work on trying to figure out how we can test that in the best way.

MSDF

It seems that people have been looking for years for the antigen or antigens that are being reacted against in MS. Can you isolate anything and try to stimulate these B cells to nail down what the antigen might be? Or because they're so hypermutable, they might react to anything and then expand on their own anyway?

Dr. Monson

Well, we know that they don't recognize all targets, right? So we just published a paper in November of this past year, actually it was October when it came out online. But what that shows is that these MS PreCISe-based antibodies bind to neurons and astrocytes in the gray matter of the human brain. And they don't bind to other tissues. They don't bind to other cell type. They are really fairly specific to neurons and glia in the brain. So we know that part of it already. But the question is, you know, what are they doing there? And is it just an epiphenomenon (is what they call it, right)? Is it just a bystander effect that we're even able to find them? So we just don't know the answers to those questions yet. But all those are good possibilities.

MSDF

Does this depend on the natural propensity of the immune system to create a lot of diversity, generate diversity, because it seems like what you're talking about are all replacement or substitution mutations within these codon hot spots? If you had a deletion or frame shift or something else, you wouldn't see it, because they're not even functional, I assume?

Dr. Monson

Right. That's exactly right. You got that right.

MSDF

Is there any value in combining MRI with the antibody gene signatures for a higher predictive power?

Dr. Monson

So let me be very clear. This test is not meant to replace MRI. MRI is a gold standard in the field. It is essential for physicians to be able to understand the disease and to come up with a plan for how to treat those patients. This is just meant to be a very powerful, supportive, preclinical diagnostic tool to help them base their decisions appropriately. So that's what we're mostly excited about. So, yeah, absolutely. Combined with MRI, I think it'll do an even better job. We actually in the clinical trial we just finished, it's not published yet, what we showed was that when you combine MS PreCISe with oligoclonal banding, the OCB test, that actually you can boost the accuracy of MS PreCISe up to 96% when you combine it with OCB. So that tells us, also, at a scientific level that not only are the genetics of the antibodies important to drive disease, but also that the antibodies probably plays a role in their conversion to MS as well.

MSDF

Based on the efficacy of rituximab that's been shown, and what you've been finding, is there any thought to doing something more permanent, like using CAR T cells to eliminate B cells almost permanently?

Dr. Monson

So as a B cell biologist, it's really somewhat offensive to think that we are going to get rid of B cells in all these people, and they're going to be able to be okay with that. We rely a lot on B cells differentiating into plasma cells and living in the bone marrow and making antibodies against things that we see all the time. But when we start depleting B cells from people long-term, it's possible that their humoral immunity, which is composed partly of the B cells and their antibody products, will not be able to fight newer infections because, you know, there's no new B cells to learn about those new infections.

So no, I don't think it's a wise decision that we continue to use rituximab and ocrelizumab. I think that they are the next step. They're a transitional stage that we need before we can get to the true gold standard, which would be a way to deplete just the B cells that are involved in pathogenesis of the disease. My stump on that would be that we should be making B cell depleting antibodies that only recognize those B cells that carry the MS PreCISe antibodies, and those are the B cells we should be getting rid of. But we have a lot of work to do to be able to show that they really are the ones that drive evolution to MS.

MSDF

What is MS PreCISe? Is this a commercial test now?

Dr. Monson

So MS PreCISe is its commercial name, but it has not been rolled out yet. It's just beginning into a CLIA lab right now. So hopefully within the next year, it will be an orderable test.

MSDF

One thing I noticed in one of your papers was you said it wasn't feasible at the time the paper was written to be doing this en masse because it was a very tedious procedure. So does this test essentially make it more feasible?

Dr. Monson

Yeah. The way we discovered MS PreCISe was actually looking at the antibody genetics of single B cells, which we sequenced using Sanger sequencing. Sanger sequencing is a very elegant immunogenetics-type method. So we spent about a year and a half re-tooling that technology to use next-generation sequencing. So now all we need to do is get a spinal fluid from a patient, and then we extract the DNA directly from that, and we sequence from the entire pool instead. And actually, what's nice about it is we also get a much deeper database from each single patient because we see all of the DNA from that sample now instead of just the few B cells we were able to sort before. It's really nice in that respect because we get a much broader idea of the repertoire. So that is what MS PreCISe is based on is being able to use next-generation sequencing now to really pull those antibody genetics out of individual patients.

MSDF

What are the unanswered questions at this point?

Dr. Monson

Well, there are a lot. But I think the one that strikes me the most is whether or not we can pull the antibody gene signature out of the blood. If we can do that, it would get rid of all these spinal fluid taps that our patients have to undergo right now. And so we're working really hard to see if we can find a way to pull them out of the blood so we don't have to do these spinal fluid samplings any more. That's probably our biggest one.

The other thing that we're really interested in, once we can find the signature in the blood, it shouldn't be too hard for us, then, to start asking questions about whether or not family members have a higher risk of getting MS. Which is probably one of the primary questions I get from patients all the time: Can you test my daughter? You know, I'm worried about her maybe getting MS someday. And so that motivates us to think, yeah, we got to get this test ready in the blood so we can start asking those kind of questions. I also think MS PreCISe will be a good monitoring tool. I mean, maybe we do keep treating patients with rituximab, but we don't re-treat them unless they're MS PreCISe score starts to creep back up again. So we're hoping that it's a way to also monitor efficacy of different drugs for that matter. So those are the things we're really working on pretty hard right now.

MSDF

Great. I appreciate it. Thanks.

Dr. Monson

Sure. Thank you.

[transition music]

MSDF

Thank you for listening to Episode Seventy-nine of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Carol Cruzan Morton. Msdiscovery.org is part of the nonprofit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is Vice President of Scientific Operations.

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

[outro music]

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

For Multiple Sclerosis Discovery, I'm Dan Keller.

Full Transcript:

[intro music]

Host – Dan Keller

Hello, and welcome to Episode Seventy-eight of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller.

A lot can be learned about pregnancy and MS by tracking pregnant women and their offspring over time. Dr. Dessa Sadovnick, a professor of medical genetics and neurology at the University of British Columbia in Canada, has started such a registry with international colleagues. I spoke with her at the World Congress of Neurology in Santiago, Chile, in November, where she described these efforts and what a very focused registry can tell us.

Interviewee – Dessa Sadovnick

I'm not talking about a general registry. What I'm talking about is a pregnancy and outcome registry. So this is not just taking people who have MS and trying to keep track of them. This is looking at actual pregnancy outcomes and what happens to the children after. So it's a very specific type of registry.

Interviewer – Dan Keller

It seems like there's a multitude of variables you can look at. What sorts of things are you going to be tracking if you get this going?

Dr. Sadovnick

Well, I think the important factor is that just because you have a disease such as multiple sclerosis doesn't mean you're immune from other factors that can affect pregnancy outcome and child development. So in addition to knowing about drug therapies, disease course, other exposures related to your MS, it's also important to know about your previous pregnancy history, your family history, your basic demographics, including your ethnic background, comorbid diseases which you may also have with the MS. All these factors can affect pregnancy outcome and child health.

MSDF

Will you be looking at the mother's longitudinally? Or only the children?

Dr. Sadovnick

Ideally, we'd like to be able to look at the mothers up to a year post-partum, and then follow the children longitudinally. Because there are situations where children do not have a certain disease that the mother may have, but over time, they might be found to have some late onset problems, for example, related to learning disabilities or something like that.

MSDF

Can you separate those out by biological cause or environmental cause? They're in a household with people who have a disease and have to deal with it.

Dr. Sadovnick

Well, we know for a fact in terms of MS that there is certainly no transmissibility within a household. We have done a lot of work over the years that show very clearly that the excess of MS you find within biological relatives of people who have MS is very clearly due to genetic sharing, not shared family environment. So from that point of view of the child inheriting MS, we're not looking at the family environment.

Obviously, there're many psychological issues and many socioeconomic issues related to having a parent who has a chronic disabling disorder. And the impact this could have on child development must, of course, be taken into consideration. But what I'm trying to look at here is more the general factors in terms of, if the mother is exposed to a disease-modifying therapy at the time of conception or in early gestation, and if there is an adverse outcome in the pregnancy, is that necessarily correlated? Or could that have happened for many other reasons?

Similarly, if the child develops problems down the road, could that be related, maybe, to the uterine environment because the mother has an autoimmune disease? Which does not mean the child gets an autoimmune disease, but maybe, in some way, it impacts the autoimmunity long-term?

MSDF

How long would you have to track children? And how many would you have to track to get meaningful numbers?

Dr. Sadovnick

Well, this is obviously always a concern, and you would have to track a sizable number. But when you consider how many people there are with MS in North America, and if you could do a centralized registry, I think it's realistic that you follow them at least for a few years after delivering. Once they start reaching their developmental milestones, you can get some ideas. But I think the main factor is that we're always saying, therapy is not indicated if you're contemplating a pregnancy. And this causes many issues for many people. But the evidence for this is so scarce. And my big concern is that, are we really being overly cautious? And we won't know this if every adverse outcome is automatically trying to be related to exposures either at conception or in the early parts of gestation.

MSDF

Pregnancy itself is immunosuppressive, but it seems women have a rebound after delivery. So what goes on with treatment during pregnancy? Is it okay to stop treatment if they're naturally going to be somewhat immunosuppressed?

Dr. Sadovnick

This is one of the big areas that we really don't have information, and we need good information. Obviously, if you look at a series of women, what seems to happen is especially in the third trimester, they seem to do better. And then, of course, once you deliver and their hormonal changes take place, there's an increase of relapses after delivery within the first three months. That's not to say women can't have relapses while they're pregnant. That is not to say that women are going to have relapses necessarily after delivery. But if you look at large numbers, this is the pattern. The question then comes up, if you have a relapse while you're pregnant, how severe is the relapse? And how should it be treated? There're no set guidelines. The same way as after delivery, a big factor is whether the mother's breastfeeding or not breastfeeding. In today's society, you're really encouraged to breastfeed, but that could have impacts on how you treat a relapse.

The other big issue in terms of pregnancy-related relapses is something that we also experience when we look at people who have MS and they're going into menopause. And that is, are the symptoms really an MS relapse? Or could they be pregnancy-related? If you have a symptom, say you have urinary problems, say you have balance problems, say you have fatigue, how do you measure if this is specifically an MS relapse versus just part of either the later stages of pregnancy, the early stages of pregnancy, or living with a newborn child? There is really nothing concrete on how to measure what's a true relapse, what's a pseudo-relapse. And there are no really specific guidelines on how to treat these symptoms during gestation and immediately after delivery. This is an area that we really need to develop.

One of the things that we have been able to do is a lot of people are interested in this topic, but it's never been looked at in a formalized manner using experts from many different areas. So about a year and a half ago, I put together a meeting of a group of people who are interested in reproduction and child health. And we received some funding to have a two-day meeting from the Canadian Institute of Health Research, as well as some money from Teva Neurosciences and Biogen Idec. And what we did is we had a two-day workshop basically saying, is there a need to learn more about this area? And if there is, how can all these specialists work together to try to develop knowledge-based information?

So we gave our little virtual network, which has no ongoing funding; it's basically people just working voluntarily. We've given it the name of MS CERCH, which is Center of Excellence for Reproduction and Child Health. And we've put together a voluntary working group. And where we're at right now is we've actually just had a paper published in Obstetrics and Gynecology, the American main journal. They also call it a Green Journal, but it's not neurology. Just talking about limitations, guidelines, what we know and what we don't know about reproduction and child health. So this was published the end of 2014.

We're currently working with the American College of Obstetrics and Gynecology to try to have our paper turned into some guidelines for people with multiple sclerosis. We've also just recently as a group published a paper talking about why there is a need for a disease-specific registry rather than a treatment-specific registry.

We are also just submitted a manuscript looking at all the issues dealing with males with MS in terms of reproduction and child health, because the focus, of course, is on females. But there're still a lot of males out there, and they face many issues that have not been addressed. And we're in the process of trying to get some funding for the first-ever grant to look prospectively at the occurrence of peripartum depression in both mothers and fathers who have multiple sclerosis, a topic that's never been looked at before. So from our two-day meeting, which was quite casual and informal, we have been able to move forward, and as a group, had some concrete outcomes. And we're hoping that we're be able to move forward with this group, hopefully obtain appropriate funding, and we're be able to, maybe, really come up with some knowledge-based information for people with MS who are contemplating reproduction.

Another major area of concern is we're more frequently now identifying the pediatric population with multiple sclerosis. The focus on this population has largely been the recognition that MS does occur in the pediatric population. But what's happening is as years are progressing, this pediatric population is evolving into a population who are capable of reproduction. How diagnosis of pediatric MS can impact not only reproductive ideas, but also just behavior in teenagers, and how all this is interrelated is not known as well. So it's a whole other area that we really need to understand.

MSDF

Are you looking for buy in from clinicians in all of North America? Or restricted to Canada? Or worldwide?

Dr. Sadovnick

Ideally, we'd like worldwide. Realistically, right now in our group, we're basically clinicians who are in Canada and the US. We have some buy in from some clinicians in Europe, and it's the obvious problem when you don't have resources, the buy in has to be voluntary. So we do have strong connections between Canada and the US, and we're working forward to try to make this a topic that is more at the forefront.

MSDF

You have a pretty good system of linked databases in Canada. Can that help you with this? I mean, you know diagnoses and pharmacy and death records and hospital visits and everything else.

Dr. Sadovnick

Linked databases are a very important resource, but they are exactly what they are: linked databases. You're not dealing with the actual people. You're dealing with how the information has been recorded. So while for some purposes linked databases are extremely important, and there's been a lot of work published out of Canada, including with our group in British Columbia using the BC record linkages. They are informative. But it's not the same as actually dealing with the actual people, because record linkage cannot tell you everything you need to know about the person.

Just to use an example in terms of pregnancy outcome. You can identify a woman who has MS. You can look at when she had prescriptions filled for her disease-modifying therapy, for example. You can look at if any birth defects were registered for the child. But what you don't know is, did this mother have previous pregnancy losses? Registries only have live births. Does the mother have a family history of some relative with a certain disease? Could the mother have comorbid diseases that for some reason are not linked into her medical history? Maybe she's moved from another country. Maybe she doesn't have the health coverage. So there's a lot of issues with record linkage. And I think it's very important to know that it has strengths and limitations. But it's not the actual end of everything.

The other issue with record linkage is it's someone's interpretation. For example, if it's recorded through record linkage that you have a given disease, it's assumed that all the appropriate diagnostic tests have been done. But is that necessarily the case? Could the person who's actually doing the coding reading from the records make that assumption? So you have to be careful.

Years ago when I started in clinical genetics, we had a BC health surveillance registry. And the idea was to basically identify any children who had been within the hospital system in the first seven years of their life. And it was a provincial recording system. But the truth of the matter was is when we went back, and I spent a lot of time working with colleagues going back and reviewing the actual forms from which the data was collected, and the amount of errors you would find. Even in something as simple as MS, looking at cause of death.

If you look at record linkage, sometimes it doesn't always note the cause of death the person had MS. Sometimes if there's asphyxia, the question is, was it just asphyxia? Is it related to the MS? Is it from something else? Another issue is very often people who have a specific disease like multiple sclerosis and they die, the real cause of death is ignored. Very often we know that cancer, for example, is underdiagnosed in a person with a specific disease like MS. Just because you're having bladder problems, it's often attributed to MS, where in fact, you could actually have bladder cancer, as an example, or bowel cancer. So if you look at all these data, I think it's important to realize that record linkage is a very useful tool, but it is not the only tool that should be used.

MSDF

Finally, where does this all stand? You mentioned that you have people doing it on a voluntary basis. Do you foresee something more formal?

Dr. Sadovnick

We're trying to get something more formal in North America. Obviously, funding is the issue. And right now we're trying to get the drug companies to realize that, if they would work together to have a proper pregnancy registry, it might be in everybody's interest, rather than just assuming that the drugs are not advised during pregnancy or when trying to conceive.

The problem with all these registries is that where does the money come from? In Canada, we have a very interesting scenario right now where they're trying to put together a registry of people who have multiple sclerosis in Canada. This has nothing to do with pregnancy. This is just, who has multiple sclerosis in Canada? A registry with minimal data sets. And this started with the Canadian Institute of Health Informatics. This has been going on for quite a few years, and I'm on both the technical and the medical advisory committee for this. But the problem is, who's going to fund it? The concept was to enlist the ministries of health to get involved and fund it, but each ministry of health has its own issues in each province, and their interests are different. So even though the concept there was to try to get a cross-Canada registry for people who have MS, funding after many years of trying is still a major obstacle.

It's a big issue, but this is why I'm hoping at least if we can focus on the idea of pregnancy, maybe through some research funding or company funding, we'll be able to at least get a pilot started that will start to answer some of these questions. A lot of money is being spent by each drug company looking at their treatment-specific pregnancy registries. And if we could get them to realize that if they all work together, we might get somewhere. It would be nice.

[transition music]

MSDF

Thank you for listening to Episode Seventy-eight of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Carol Cruzan Morton. Msdiscovery.org is part of the nonprofit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is Vice President of Scientific Operations.

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

[outro music]

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

For Multiple Sclerosis Discovery, I'm Dan Keller.

Full transcript:

[intro music]

Host — Dan Keller

Hello, and welcome to Episode Seventy-seven of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller.

Pregnancy and the postpartum period present special concerns to women with MS. Dr. Annette Langer-Gould, a neurologist and epidemiologist at Kaiser Permanente in Los Angeles, investigates ways to lessen the risk of relapses in these women. We discussed the effects of breastfeeding, among other topics, when we met at the ECTRIMS meeting last fall in Barcelona.

Interviewer – Dan Keller

In terms of pregnancy and breastfeeding in MS, what are you looking at?

Interviewee – Annette Langer-Gould

We're studying modifiable risk factors for postpartum relapses in women with multiple sclerosis. And specifically, we are looking at starting therapy shortly after delivery, whether that can reduce the risk of postpartum relapses, whether breastfeeding, particularly breastfeeding exclusively, could reduce the risk of postpartum relapses, and whether vitamin D levels play any role in increasing or decreasing the risk of postpartum relapses.

MSDF

And are these women who are on disease-modifying therapy throughout pregnancy or not?

Dr. Langer-Gould

No. In our population, a little over 60% were treated prior to pregnancy. But we do have a decent number of women who had decided to never go on disease-modifying therapies before, and almost all of them stopped disease-modifying therapies either shortly before or when they find out that they're pregnant.

MSDF

In terms of each of those outcomes, what are you finding?

Dr. Langer-Gould

We haven't analyzed the data for the vitamin D yet, but in the German pregnancy registry, we just published the data in exclusive breastfeeding, and once again showed that exclusive breastfeeding does protect against postpartum relapses. In that population, actually 96% of the women had been on some sort of DMT prior to pregnancy, and none of them were treated throughout pregnancy. We also found that resuming DMTs does not seem to have a big effect on reducing the risk of relapses, particularly in the first six months postpartum.

MSDF

Is that in women who are exclusively breastfeeding or not?

Dr. Langer-Gould

Ah, so that's a good question. So there is no good safety data on taking the medications during breastfeeding. And therefore, many clinicians and most patients are concerned about potential theoretical risks. So behaviors are actually mutually exclusive. Women typically will either breastfeed or resume medications early in the postpartum course. The other thing we find in the Kaiser population is that there are still a fair number of women who neither breastfeed exclusively or resume their medications, which presents sort of an interesting opportunity. If we could show that one or the other behaviors is protective, perhaps we could encourage either exclusive breastfeeding or resuming DMT.

MSDF

If women are not breastfeeding, do you have an idea of the time course of resumption of risk for relapse?

Dr. Langer-Gould

Yes, so the concern about postpartum relapses really is about having a relapse in the first three to four months postpartum. If we look over at the whole pregnancy year, and that's about 30% to 40% of women. So this is actually still the best defined risk period for having a relapse and actually the only clear trigger—with perhaps the exception of upper respiratory tract infections—of relapses. So we know that having just had a baby or having an upper respiratory tract infection is a pretty strong predictor of having a relapse. So it presents sort of a unique opportunity to also look at other biological factors, like vitamin D, which is why we're interested in it, to see if any of these things have a strong role in relapses as well.

MSDF

If women are breastfeeding postpartum, what is the hormonal profile like? Is this almost like an extension of pregnancy?

Dr. Langer-Gould

For women who breastfeed exclusively, meaning that they breastfeed to the point of suppressing their ovaries and not resuming menstruation—so that essentially there's no regular meal that's being replaced by formula or by table food in the baby—they have very high prolactin levels. So it's actually a little bit different than being postmenopausal, in the sense that they have very high prolactin levels. And they have incredibly low nonpulsatile FSH and LH levels. In the postmenopausal period, there occurs a very high FSH and LH levels. The similarity, though, is that they both have bottomed-out estradiol and progesterone levels, in both women who are breastfeeding to the point of suppressing menses and also postmenopausal women. And of course the other similarity is that there's no ovulation occurring, either during pregnancy, during exclusive breastfeeding, or after menopause.

MSDF

So it sounds like breastfeeding is really a hypothalamic pituitary suppressant as opposed to in menopause, where you still have those cranking away, but just no response from the ovaries.

Dr. Langer-Gould

Correct.

MSDF

Can this be used in any clinical sense? Do you see an application?

Dr. Langer-Gould

The most obvious direct way to translate these findings is that that, if you have a woman with MS in front of you and she is pregnant and she tells you she'd like to breastfeed, we certainly have no good reason to discourage her. And that if anything, I would suggest that the data we've already published would point to the fact that we may want to encourage exclusive breastfeeding, provide them with lactation counseling, and also sort out exactly what the optimal duration of exclusive breastfeeding may be for these women. Is it really only eight weeks, which we had defined arbitrarily? Or does longer duration of exclusive breastfeeding have additional suppressive properties? And that would, of course, have implications in the United States for things like maternity leave and work accommodations to allow that to continue, if it has a strong therapeutic effect for the mother.

MSDF

What's the relapse rate among postmenopausal women compared to postpartum women?

Dr. Langer-Gould

So relapse rate declines with age. And so it typically in postmenopausal women, although there's not great data, we would expect them to have relapse rates of less than 0.3 per year, Annualized relapse rates of less than 0.3 per year. And in postpartum women, that first three to four months, the annualized relapse rate exceeds one.

MSDF

But men also have a decline in relapse rate as they age, too. So you can't attribute it to lower estradiol.

Dr. Langer-Gould

Exactly. Yeah, I think it's far more complicated than just a simple sex hormone effect. You know, that was sort of our first instinct from pregnancy or the reason pregnancy must be protective. It has to have something to do with estradiol or the very high progesterone levels. And that's what prompted the postpartum study and also the estradiol randomized control trial. And both of those, of course, disappointingly have been negative. In isolation, the sex hormones associated with the protective effect of pregnancy don't really have a protective effect on inflammation. It's probably more of a combination of factors that play into modulating the immune response.

MSDF

Where do you go from here?

Dr. Langer-Gould

I think that if we are able to reproduce the findings, looking at this population-based source, that early resumption of DMTs is not particularly helpful, but perhaps it may be later in the postpartum year, and that exclusive breastfeeding is, again, protective, then I think the next step really is to establish the safety of some of these medications during lactation. For several of them, there's really no biologically plausible reason to think that they would have an effect on the baby, as they're not likely to be absorbed through the gut or enter into the baby's bloodstream.

Examples of that would be the large molecules like Copaxone, the interferons, and also the infusion medications, Tysabri (natalizumab), and rituximab as well. Although you may be able to detect them in breast milk, they are such large molecules that they would not diffuse across the baby's stomach and into the bloodstream. Think about it. If the mom has to take it as a pill, it is very likely to be transmitted to the baby. If the mom has to take it as an infusion or injection, very unlikely that oral route through the baby would have any effect.

MSDF

How sensitive is this effect to, as you said, exclusive breastfeeding? Can you start introducing formula, or it's all or none?

Dr. Langer-Gould

That's a really good question. So we did look at that also in the German pregnancy registry. So first of all, women tend to have very defined behavior. They tend to decide to supplemental feed with formula very, very early, before they've even established their full milk supply. So to back up even further, a healthy woman gives birth to her child. Usually menstruation will resume two months after delivery, not one month. So it does take the HPA gonadal axis a little chance to recover from those high-circulating hormones of pregnancy. And in women who introduce supplemental feedings, particularly early, we also see the very same thing; that they will resume their period at two months postpartum.

Actually, most of the work done in this field has been done by nutritionists who are in developing countries who are interested in knowing what you should do if you see a starving mother and a starving baby. Who should you feed?

It turns out that if you feed the baby, the mother's ovarian function will resume. So any regular supplemental feedings and very quickly their prolactin levels will drop. The pulsatility of the FSH and LH secretion will return. Ovulation returns, and so does menses. It's essentially sending the mother's body a signal that the baby no longer needs nutrition from the mom to survive, so she's ready to have another child. So the right thing to do in that situation would be feed the mom, and let her nurse the child. Biologically, it's very interesting. Even though some breastfeeding is better than none for the baby, in terms of the effect on the mother's HP [hypothalamic-pituitary] ovarian axis, some supplemental feeding is just like all supplemental feeding.

MSDF

Have we missed anything or anything interesting to add?

Dr. Langer-Gould

So I guess I would say just in general, women's, and now even men's, desire to have naturally-born children has taken on a new significance with a lot of the small molecule agents, because we need to consider family planning and discuss it much earlier, as small molecules are likely to have an effect even if they get pregnant accidentally on the developing fetus. This is a challenge we haven't had before, because large molecules won't cross the placenta in the first trimester. And the first trimester is the critical period for organ development.

So it's sort of new era for MS neurologists, where we really, really have to think carefully about which medication we put them on if they're planning on having children soon. So I’d strongly encourage that you have that conversation very early and have it with every followup visit. I typically will ask them, are you planning on having children within the next two years? And if they say, no, I ask what kind of birth control they're on, or in some cases they're in same-sex couples. That's obviously an exception. And if they are not on a reliable form of birth control, I think you need to think twice about giving the small-molecule agents—so the pills, basically.

MSDF

Should MS neurologists work with high-risk OB/GYNs?

Dr. Langer-Gould

I think for the most part it's not necessary, because women with MS, they don't have abnormal complications at pregnancy. I think there are certainly situations that we're running into now. If they get pregnant accidentally on fingolimod, teriflunomide, or Tysabri, we do need to work with them, mostly for the baby. So you may want to do more intense early screening if the mother is culturally open to the idea of having an abortion. You may want to do more fetal ultrasounds, perhaps even a fetal MRI, if there's suspicion of major malformations early on in pregnancy.

And also for the Tysabri, really, it's not so much about organogenesis, but if they've had later exposure to Tysabri during pregnancy, which unfortunately on occasion has been necessary to control rebound disease activity during pregnancy, that, you know, we have seen hematological abnormalities in some of these children, so far none with clinical complications. Only one child had a subclinical intraventricular hemorrhage that resolved. It's still concerning. Our experience is very small, and we would certainly highly recommend that those women give birth in a hospital that has a neonatal intensive care unit available and a pediatrician on call to examine the child and also make sure that the child doesn't have a severe thrombocytopenia or anemia at birth.

MSDF

Do the different drugs have different risks for fetal malformations or other dysfunctions?

Dr. Langer-Gould

Yes. So teriflunomide, or Aubagio, is the most concerning medication because if a woman gets pregnant on that accidentally, it is, you know, a category X drug because it can interfere with neural tube development. And although you can chelate to get the medication out very quickly, the safety data from other indications, you know, the rheumatoid arthritis and lupus literature, is not particularly reassuring in terms of fetal outcomes. So I think that's sort of the number one to stay away from if a woman is planning on getting pregnant. And it's also one where, you know, there is some concern, although not strong evidence, that it may also affect the offspring of men with MS who are on the medication.

In terms of the other ones, of course, again, small molecules in fingolimod has about a 15% to 16% major fetal malformation risk with early pregnancy exposure. It has a very long half-life. So even if they stop the medicine the minute they find out they're pregnant, it takes over two months for it to be cleared, which means that the baby has seen it now through the entire first trimester. That can have significant effects, both on cardiac and brain development. And then with dimethyl fumarate, we haven't seen—now of course, this is a very new drug, so we don't have nearly as much experience—we have not seen any major malformations, but there was concern in the animal models that it could interfere with cognitive development. In particular, the rats had maze-finding difficulty.

MSDF

Is alemtuzumab indicated at all? It seems to have a long tail.

Dr. Langer-Gould

I'm not sure what the half-life of alemtuzumab, but it's probably similar to other monoclonal antibodies, which is usually around 15 to 20 days. So monoclonal antibodies don't cross the placenta in the first trimester, because it's a very large molecule. So large molecules only get across if there's an active transport system. For antibodies, there is an active transport system, because it's very important that the child be born with a high dose of antibodies received from the mother to help protect them during the early part of their infancy while their own immune system is still developing.

So we see maternal antibodies being transported, and of course, monoclonal antibody medications would be dragged along with that during second trimester. And it goes up in elliptical fashion, with very, very high amounts being pumped across the placenta in third trimester. And they also, of course, have a very delayed clearance mechanism, both the fetus really has no clearance mechanism, and then even the neonate has a very slow clearance mechanism. So in TNF alpha studies, if the drug is given during third trimester, it's typically not cleared until about six to nine months postpartum.

So you also have to be concerned that a baby exposed would have some of that medication hanging around during the early neonatal period and give some thought to whether or not their immunization scheme would need to be adjusted, as the cautionary tale there would be TNF alpha exposure during pregnancy.

There was a case reported of a woman who had very severe rheumatological disease, had discussed with her rheumatologist the potential risks and benefits of taking it throughout pregnancy, opted to take it throughout pregnancy. And then living in an endemic area for tuberculosis, the baby got the BCG vaccine and got disseminated mycobacterium and died. And that, you know, was probably directly related to impaired immunity from the TNF alpha antagonist. And sure enough, the baby was born with fairly high cord levels and also had very high levels still remaining in the blood in the neonatal period.

So it's not just once the baby's born, it's like the drug is out. So drugs like alemtuzumab and rituximab, the way in which they work, even though the drug could be long gone, but the effect of the medication works very long time. So those are actually good choices for women with highly active disease who are planning on getting pregnant. And you have concerns about rebound. I mean, we typically use rituximab because it's obviously much safer than alemtuzumab and seems to do a fairly good job. But you know, these aren't medications we should be giving while they're pregnant, but probably not a big effect in crossing the placenta and on the baby if they're used prior to pregnancy.

MSDF

If they can plan that well and get a pulse of that early, and then get pregnant a few months later.

Dr. Langer-Gould

Yes. Yeah, that's always the trick, right? And they do get pregnant accidentally on just about everything we put them on. So the infrequent infusion medications is the easiest because you can ask about last menstrual period. And you can ask about birth control use, and you can do a pregnancy test the day of, a quick urine dipstick and find out so that you don't accidentally infuse a pregnant woman. Of course with Tysabri, when you're giving them an infusion every month, it gets a little tricky. Usually people just kind of get tired of it. The nurses forget. The doctor forgets to order it, although it's not necessarily bad practice if you know you have a patient who is not on a reliable form of birth control.

MSDF

Very good. I appreciate it. Thank you.

Dr. Langer-Gould

You're welcome.

[transition music]

MSDF

Thank you for listening to Episode Seventy-seven of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Carol Cruzan Morton. Msdiscovery.org is part of the nonprofit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is Vice President of Scientific Operations.

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

[outro music]

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

For Multiple Sclerosis Discovery, I'm Dan Keller.

FULL TRANSCRIPT:

[intro music]

Host — Dan Keller

Hello, and welcome to Episode Seventy-six of MultipleSclerosisDiscovery, the podcast of the MS Discovery Forum. I’mDanKeller.

Pregnancy presents special considerations for women withMS.Beyond the medical and pharmacological issues, there aresocial,socioeconomic, and parenting concerns. Dr. Dessa Sadovnick,aprofessor of medical genetics and neurology at the UniversityofBritish Columbia in Canada, spoke on issues ranging frompregnancyplanning through the postpartum period at the WorldCongress ofNeurology in Santiago, Chile, in November, where we metup.

Interviewer – Dan Keller

Let's talk about gender and hormonal issues in pregnancy.Whatare some of the things you're looking at now?

Interviewee – Dessa Sadovnick

Well, in terms of gender, it's really been interesting thefactthat initially it was actually thought that men may have MSmoreoften than females. And now, of course, it's very wellestablished,as with many other autoimmune diseases, that femalesare affectedmuch more than males. The question is why? And there'sa lot ofresearch being done into hormones, especially theestrogens, theestradiols, to try to see how that relates to diseaseonset,clinical course, etc. But again, there's no reallyfirmanswers.

We do know that the hormonal changes during pregnancy do seemtoreduce the number of relapses during gestation, and as soon asyoudeliver, the relapse rate goes up very high. So this is one areaofbig interest. There's been some recent work published onmenopause,and it does not seem that women who have MS havemenopause earlierthan other women or later than other women. Theredoesn'tnecessarily seem to be a direct effect between clinicalcourse andmenopause, other than to say that a lot of the symptomsdo overlap.So you have to be very careful, as a clinician, todecide whetheryou're talking about MS-related symptoms or symptomsthat might beamenable to treatment just for regular menopause.

Puberty is a very key period in MS. We know that you can getMSprior to puberty, but it is recognized now in thepediatricpopulation that the group who have it prior to puberty dohave amore similar female to male ratio. It's only once pubertyhits thatyou have the excess in the females.

MSDF

Does pregnancy permanently change physiology compared tothepre-pregnant state, or do people go back to their baselinerelapserisk after some point?

Dr. Sadovnick

There is no evidence to say that having a pregnancy willchangeyour long-term course or your outcome after a given period oftime.It seems like people on the whole, and everything is always onthewhole because there's always the exception, but in general,youtend to go back to what you were like before, taking intoaccountthat, after pregnancy, you'll have had a longer diseaseduration.Just an example, if it takes you a year to becomepregnant, thennine months pregnancy, three months postpartum, thenext time youlook at it you're two years since before you tried toget pregnant;so you're two years more into the disease. But there'sno evidencethat pregnancy harms the long-term outcome of MS, andthere's noevidence that not getting pregnant is beneficial forwomeneither.

MSDF

Is there a physiologic explanation for the higher relapserateafter pregnancy? Is it easily identified, or is itprettyhypothetical?

Dr. Sadovnick

Well, it's thought to be related to the changes in hormonesassoon as a woman delivers. But there's nothing that can mark ittosay this woman's going to get it, this woman's not going tohaveit. You know, there's no marker that's going to say who's goingtohave a relapse after delivery, who isn't.

MSDF

Even though there's not much data right now about many ofthedrugs used in MS and pregnancy, women are advised oftentimes nottobe on the drugs, but they also don't immediately get pregnant.Sodo they have a long period potentially of risk of relapse, anddoesthat affect the long-term course eventually?

Dr. Sadovnick

Well, there's been controversy in the literature aboutwhetherthe number of relapses a woman has while shehasrelapsing-remitting MS affects her emergence intosecondaryprogressive MS. So there's been controversy at thefindings aboutwhether the number of relapses predicts how soonyou're going to gointo a progressive phase or not. As far as I'maware, the mostrecent information suggests that they might be twoindependentfactors. So, it's a hard question to answer.

Obviously, the drugs don't cure MS. So it's not that you'regoingto prevent MS by taking the drugs or stop MS dead in itscourse bytaking the drugs. You're taking a risk. [With] anyrelapse, youdon't know whether there's going to be a completerecovery or apartial recovery. The more relapses you have, theharder everythingis in day-to-day life and coping and recovery,and getting pregnantis not something that happens instantaneously.So it's a bigdecision that women do have to make. And there's noreal easy answerfor saying who will do well being off themedication for awhile, whowon't do well being off for awhile.

It's an informed decision that people have to make. And wesayit's very important that if you're planning a pregnancy, toreallylook at all the information that's relevant to yourparticularsituation and make an informed decision about yoursituation.There's no general answer for everybody. And we've comeup withsome reproductive counseling models that deal with the wholeareaof reproduction and reproductive planning.

Now, one thing that I find that people often don't tend tothinkabout is that they think of getting pregnant in termsofconceiving, having a pregnancy, delivering, and the threemonthspostpartum. But they forget the fact that once you do have achild,there's a lot of commitment you have for a long timemovingforward. It's not just your three-month postpartum relapseratethat you're concerned about. And people have to be verycognizantthat if they do have a chronic disorder, that this willhave someimpact on their socioeconomic status, on their ability toparent,on relationships; all this has to be taken into account. Andtwo ofthe things that we often say to people who are planning apregnancyis: One, remember that it's a long-term commitment; andtwo, as aparent, instead of focusing so much on what youcan't dobecause you're a parent who has MS, maybe youshould focus more onwhat you can do. And I think that's avery good attitudeto have.

I remember many years ago we had a woman who was just soupset,because in the city she lived in there was a big annualfestivalfair every year. And she'd take her children there, and bythe endof the day she was hot, she was tired, she'd have a relapse,she'dbe in bed, but she felt it was her duty, as a parent, to takethechildren to this festival. So we just talked about it fromapractical point of view, nothing specifically medical oranythinglike that. And said, well, what would happen if you wentwith yourkids with someone else; you stayed in a nice shady place,you had,you know, something cold to drink. Your kids went off anddid allthe running around, and then they'd come back and report toyouwhat they're doing. And, you know, try a day like that insteadofyou're being the one to kill yourself running around with themtoall the activities. And she came back to the clinic a coupleofyears later, and she says, you know, it was such a difference.Thekids had a good time, and instead of my being in bed for thenexttwo weeks, we went out for dinner after, and lifecontinued.

So I think that that's so important when you're talkingaboutplanning pregnancies is you have to think forward. You knowthatfor anybody having a baby in the newborn period, it's tiring,it'sstressful, not only for just the mother, but also for thefatherwhether he has MS or not. So if you know this is going tohappen,before you get to the point where you're in such a stateofexhaustion and relapses start happening, maybe plan ahead.Noteverybody can afford nannies or housekeepers or things likethat;that's a fact of life. But there's nothing to say you can'ttalk tofriends and work out a system where you get a bit of extrahelp inadvance, not just wait till you hit the crisis mode.

MSDF

And I suppose in the early postpartum period you could beverysleep-deprived.

Dr. Sadovnick

You can be very sleep-deprived, and then you have tostartthinking. If you're a father whose wife has just had a baby,maybeyou should try to sleep in a different room, not worryaboutgetting up when the baby gets up during the night. If you'reamother who has MS, maybe you want to reconsiderbreastfeeding.Maybe you want to consider expressing, so that you'renot upconstantly with the baby. You have to be practical. And Ithinkthat that is the big factor is: in theory there's so manythingsyou're supposed to do, but you actually have to be practical.Thefatigue component with a newborn is not going to go awayregardlessof if you have MS or not. So if you know in advance youhave MS,and it's going to be more of an issue, why not try to makesomepractical plans?

MSDF

You had mentioned the changing sex ratio mainly becausemorewomen are being diagnosed with MS. Is it that there is more MSorbetter diagnosis or some other reason for this increase inthegender ratio with women predominating?

Dr. Sadovnick

Looking at it in terms of a gender ratio, you're basicallytakingout factors, such as improved diagnostic techniques. So whatwe'restarting to think is that females react differently toenvironmentaltriggers than do males, and this could be a reasonfor the increasein females. Women are living a very different lifetoday than theydid even 30 years ago in terms of occupation, beingout of thehouse, exposures. Women react differently to vitamin D.Women havedifferent smoking habits in reacting. So we're thinkingthat what'shappening is that the female is actually responding toenvironmentalfactors in a different way now or being exposed morethan she wasmaybe a few decades ago.

MSDF

Do women live proportionately longer with MS? Could they justbegetting older, and the men aren't getting as old, and thatchangesthe ratio at that end of the spectrum?

Dr. Sadovnick

Life expectancy does not really seem to be dramaticallyalteredin multiple sclerosis for males or for females. We've donestudieswith actuarians from life insurance companies looking atthis, andMS really doesn't kill you. So I don't think lifeexpectancy is afactor.

MSDF

Anything interesting or important to add?

Dr. Sadovnick

Well, I think that a big difference is that there used to bealong lag time from the onset of the MS symptoms until youwerediagnosed. So a lot of life decisions, whether it wasdating,partnering, reproduction, or in that period when you reallydidn'tknow that you had a diagnosis, so in many ways ignorance wasbliss.You didn't really have to make decisions.

Now, of course, with the new techniques, people aregettingdiagnosed so much earlier in the disease. And they're beingtoldthat you have MS, you'll do fine, you know, there are therapiesyoucan try. You're still a person who has a life to lead. You'renotan MS patient for your whole life. So but every decision theymakethey have to go out and decide disclosure and how to deal withthefact that they now have a diagnosis. It's not this periodofignorance is bliss. So let's just take, again, going back tothepediatric example: you're a teenage, you're in university,you'reon the dating scene. When do you tell someone you have MS, doyoutell them? Do you not tell them? You're someone who's in their20s:you have a diagnosis of MS, you're dating, you talk abouthaving apermanent relationship and going on to have childrentogether. Whendo you drop the bomb that you have MS? When do youtell it toemployers? When do you tell it to in-laws? You know, whendo yousay this? That period of being ignorant is really gone now.And so,how you react, how society reacts, is something that wereally haveto look at now. When do you disclose? When don't youdisclose? It'sa very big issue.

MSDF

Very good. Thank you.

[transition music]

MSDF

Thank you for listening to Episode Seventy-six ofMultipleSclerosis Discovery. This podcast was produced by the MSDiscoveryForum, MSDF, the premier source of independent news andinformationon MS research. MSDF’s executive editor is Carol CruzanMorton.Msdiscovery.org is part of the nonprofit Accelerated CureProjectfor Multiple Sclerosis. Robert McBurney is our President andCEO,and Hollie Schmidt is Vice President of ScientificOperations.

Msdiscovery.org aims to focus attention on what is known andnotyet known about the causes of MS and related conditions,theirpathological mechanisms, and potential ways to intervene.Bycommunicating this information in a way that builds bridgesamongdifferent disciplines, we hope to open new routestowardsignificant clinical advances.

[outro music]

We’re interested in your opinions. Please join the discussiononone of our online forums or send comments, criticisms,andsuggestions to editor@msdiscovery.org.

For Multiple Sclerosis Discovery, I'm Dan Keller.

[intro music]

Host – Dan Keller

Hello, and welcome to Episode Seventy-five of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller.

Today's interview features Elaine Kingwell, a research associate at the University of British Columbia in Canada. She and her colleagues have gathered and recently published incidence and prevalence figures for people with MS in the province. I spoke with Dr. Kingwell at the ECTRIMS meeting in Barcelona in October to find out the reason for the study and to explore the changing trends she found and their significance.

Interviewer – Dan Keller

What prompted you to do this study?

Interviewee – Elaine Kingwell

In British Columbia, we know that Canada has got a high incidence and prevalence rate of MS, but we don't actually have the numbers, so we've been doing a lot of research on MS in British Columbia for many, many years. But we don't have the incidence numbers for BC, and also the prevalence is out of date – the estimates that we have – so it really was time to get an idea on how many people we have in BC. And also, we wanted to look at change over time, and we have access to some amazing administrative databases in BC and also had some algorithms that we could use that have been validated, so that we could identify people with MS in the databases.

MSDF

Why are these numbers important?

Dr. Kingwell

It's important for lots of different reasons. For instance, it's important to monitor trends over time. We're able to do that in BC, because we have data going back several years. And so, it's important to see if populations are changing, so that we can get some clues about whether environmental factors might be changing. And also, for the prevalence estimates, it's important to know how many people have MS in the province, so that healthcare planning can be done wisely and resources.

MSDF

How do you go about looking at this?

Dr. Kingwell

So as I mentioned, we did use the health administrative databases in BC, which are big databases that collect data on the whole population. A number of different databases were combined, including hospital admissions and physician visits. It's all claims data, so that when someone goes to see their physician, a billing claim gets put in with their diagnosis. So we use these codes to identify people with MS. And we basically estimated the number of people with MS [over] several years – one year at a time – so that we could look at change over time for prevalence. And we also estimated the incidence, the number of new cases each year, starting in '96 right up until 2008.

MSDF

What did you find in terms of incidence and prevalence?

Dr. Kingwell

Well we found the incidence and prevalence are both high. The incidence was around 7.8 per 100,000 per year, and the prevalence was around 180 to 200 per 100,000 in 2008. So they were both high, what is relatively high compared to other places in the world and similar to rates that have been found in Europe, in Northern Europe, and other parts of Canada, as well.

MSDF

And the prevalence is increasing over time?

Dr. Kingwell

Yeah, we found that it increased quite significantly by about 4.7% per year, so a big increase. It also shifted in the predominant age of people, so that the peak prevalence age was around in the mid-40s in the 1990s, and it's now shifted up into the mid-50s. So the population of people with MS is getting older in BC. We also saw with incidence … quite differently, the incidence was not changing over time, so it stayed relatively stable; it did fluctuate as incidence always does. But over time, on average, it stayed the same.

MSDF

Are those two pieces combined—increasing prevalence and older age—good news?

Dr. Kingwell

I don't know if any of it's good news. It means that we have an older population that are probably requiring more care, as they get older, for the MS, as well as, of course, comorbidities they may have. So, it's certainly something that healthcare planners need to be aware of. And we have an aging population, in general, in Canada, as we do in other parts of the world, but we have a lot more people with MS at an older age.

MSDF

But doesn't that mean they're surviving longer?

Dr. Kingwell

That's the good news part, yeah. And it does mean that, because we're not seeing a change in incidence, the most likely explanation is that the survival is better. People are surviving longer with MS. We're seeing an increase in survival for the whole population, but we're also seeing an increase in survival for people with MS.

MSDF

What about the gender ratio in terms of prevalence but also in terms of survival?

Dr. Kingwell

We're seeing a gradual increase in the number of women relative to men in prevalence. That's most likely due to the fact that women do survive longer than men, on average, of course that's highly variable. But on average, they survive longer than men. And so, if you've got an aging population and three-quarters of the people with MS are women, then you're going to find the number of women are increasing.

MSDF

How did the socioeconomic status affect the findings?

Dr. Kingwell

Yeah, so we did actually look at socioeconomic status. It was measured at the neighborhood level, so not the individual level. It's linked into the databases by postal code. We did find that there were more people with MS in the higher levels of socioeconomic status, but the absolute differences were not that great. And, when we looked at this, it was not linked or adjusted for other factors. So there's so many things that can be attached to socioeconomic status and, of course, age is one of them, and your age is greatly related to whether you have MS or not. And so, there are other possible explanations, so we don't put a lot of emphasis on that. When we look at socioeconomic status, we really think that you need to design a study specifically to look at that.

MSDF

Could you look at the use of disease-modifying drugs according to socioeconomic status?

Dr. Kingwell

We could, and we have actually looked at that in other studies. Again, as a kind of an adjustment factor or something to bear in mind when we're looking at lots of variables at once, we find there's the same kind of trend that people in the higher levels tend to be on drug more often. But again, the absolute numbers are very small, and it could totally be related to age or other factors that are not adjusted in.

MSDF

Were the data there to be able to look at early initiation of disease-modifying drugs and any effects it may have had?

Dr. Kingwell

Well for this particular study – in the incidence and prevalence study – we looked at just whether people had ever had drug. We looked at the incident population to see if they'd had it in the last three years or so—that's the three years from their first claim, which is close to when they're first diagnosed or recognized as having MS. And for the prevalent population, we looked at whether they'd ever had MS. So we were able to tell that about a third of the cases had had a disease-modifying drug. And this study did start way back in the early 90s and then mid-90s for the incidence cases. So, you would expect it to be a lower rate because the drugs were just starting to become available in the mid-90s. So we didn't look at the actual start date of the drug for this particular study; we certainly are able to look at that because we have access to the databases to look at those kinds of questions, and we are looking at those kinds of questions in other studies.

MSDF

Can you put your findings in context to other studies at other latitudes, locals, healthcare systems?

Dr. Kingwell

Yeah, that's a complicated question. Certainly as studies are similar to the findings from some other studies. In particular, in Canada, there's been some very similar studies done in Manitoba and Nova Scotia where we've used exactly the same algorithm that was validated in those provinces led by Dr. Ruth Ann Marrie from the University of Manitoba. So, we found that prevalence and incidence estimates are very similar, and the findings and the change over time are also very comparable. When we look at some of the other countries, there are some similar findings in other places, but they vary a lot. When it comes to latitude, of course, we didn't have a big latitude gradient in our study; we were just looking in BC, and most of the people in BC live in one area around they're concentrated in the south of the province. But certainly there's a lot of variation in findings. But in order to get a look at the change over time, you really need to look within the same population on more than one occasion rather than comparing between populations over time. It's really difficult to make that comparison.

MSDF

Do you have a particularly good situation in BC in that you can link databases of diagnostic codes, physician visits, hospitalizations, pharmacy benefits, things like that that may not exist in other places with a less coordinated system?

Dr. Kingwell

Yeah, definitely. We are in a situation where we have access to some amazing databases. Many of the provinces in Canada have the same or similar databases, so it is like that. We also have the great situation that we have a clinical database in BC too where we've been collecting data on MS patients over a very long period of time. And we can link that data into the administrative databases, so we have the depth of the clinical data that we can link in the breadth of the administrative data, which has really put us in a very strong position to look at these long-term followup studies.

MSDF

Is it pretty smooth to be able to delve into these databases, or do you have any regulatory barriers like, in the US, we have all these HIPAA things. Do you have a problem with de-identifying or anything like that?

Dr. Kingwell

It's certainly not smooth. It can actually take us several years to access this data. It's a long process. It's a lot of paperwork for all of the reasons that…or some of the reasons you just mentioned. The data is actually all handled through…when we're at UBC, it's handled through Population Data BC, which is kind of the center between the Ministry of Health and the databases. And they strip all the identifiers off, so that by the time we receive any data … we, of course, have to go through a lot of privacy concerns and justification before we get any data sets. All the names and the numbers are removed, so that we don't know who anybody is in our database. Even when we're linking our clinical data, of course, everything is completely anonymized by the time we work on anything like that.

MSDF

What kind of conclusions can you draw from what you've found so far?

Dr. Kingwell

One of the main conclusions, I think, is that the incident population has leveled off, apparently, in BC. We started measuring incidence in 1996, and it's possible there were changes in incidence before that, but we can say that in the last 13 years – up to 2008 – that the number of cases has leveled off, which is good news it's not increasing. We also can say that the number of prevalent cases, on the other hand, is increasing a lot, so that the services need to be aware of that that there's going to be a demand on the healthcare system, there already is. And also that our results are very similar to as seen in other parts of Canada and comparable.

The other main conclusion I would draw is that this study really shows how you can utilize these types of databases and reliable algorithms and ways of identifying people with MS in order to monitor the number of people and also changes over time. And also can give us some information about the people with MS and what kinds of drugs they're taking because we're linked into the PharmaNet databases, and we can do that too. So there's lots of questions we can answer about the population in British Columbia.

[transition music]

MSDF

Thank you for listening to Episode Seventy-five of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Carol Cruzan Morton. Msdiscovery.org is part of the nonprofit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is Vice President of Scientific Operations.

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

[outro music]

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

For Multiple Sclerosis Discovery, I'm Dan Keller.

[intro music]

Host – Dan Keller

Hello, and welcome to Episode Seventy-four of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller.

Today's interview features Dr. Markus Reindl, an Associate Professor of Neuroscience at Innsbruck Medical University in Innsbruck, Austria. We discuss autoantibodies to myelin oligodendrocyte glycoprotein, or MOG, a protein component of myelin. These anti-MOG antibodies are particularly important in pediatric demyelinating diseases.

Interviewer – Dan Keller

First of all, why don't you define MOG for our audience.

Interviewee – Markus Reindl

MOG is myelin oligodendrocyte glycoprotein, and it's a myelin protein which was discovered about 30 years ago. It is of enormous interest to people working in neuroimmunology, because it's one of the main autoantigens used in experimental models for multiple sclerosis. And about 20 to 30 years ago, a lot of people started to work on autoantibodies against MOG in the field of MS because it was suspected to be a key autoantigen. And at that time, there were a lot of papers published with somewhat contradictory results.

About five years, six years ago, the interest of MOG was rediscovered again when people developed more specific assays to detect these antibodies. And surprisingly, it was found that they're not present in classical multiple sclerosis but rather in pediatric demyelinating diseases, such as acute disseminated encephalomyelitis, ADEM, or neuromyelitis spectrum disorders.

MSDF

And what does finding anti-MOG antibodies tell you?

Dr. Reindl

At the moment, it just tells you that if you have these antibodies the risk that you develop MS is minor. So it points to the direction of a different demyelinating disease, which is in most cases monophasic with a good outcome. Or if it's recurrent, it's often recurrent optic neuritis on multiphasic ADEM. Altogether, all this with a good recovery from relapse. Severe disease causes are rare.

MSDF

So in the early stages of MS – something like clinically isolated syndrome – does MOG tell you which direction to go in if you find it?

Dr. Reindl

Usually if you have a clinically isolated syndrome that fulfills the current criteria for multiple sclerosis, looking at the MRI or at the cerebrospinal fluid, it will typically be negative for MOG and autoantibodies, so it's just an exclusion criteria. If you look at the CIS [clinically isolated syndrome], whether it could go to the direction of multiple sclerosis or not, if MOG antibodies are present, the answer would be rather not.

MSDF

Does it fit into neuromyelitis optica, especially seronegative, where there's no anti-aquaporin-4 antibodies?

Dr. Reindl

Yes, it can also be observed in cases with neuromyelitis optica that are aquaporin-4 antibodies negative, particularly in pediatric cases, and often in cases that present with simultaneous optic neuritis and transverse myelitis at onset. So the classical description of neuromyelitis optica by Devic back in the 19th century would rather have been a MOG antibody positive case than an aquaporin-4 antibody positive case. And the pathology of both diseases is entirely different. So in aquaporin-4 mediated neuromyelitis optica, you have an astrocytopathy under high risk of future relapses and disease deterioration. Whereas in the case of MOG antibodies, it's often monophasic, and the recovery is much better.

MSDF

So it sounds like anti-MOG antibodies are not just a marker, but they're actually pathognomonic or pathogenic of the disease.

Dr. Reindl

This is currently under investigation. So what we know from neuropathology there are currently five cases – if I'm correct, or as far as I know – that have been analyzed for neuropathology. These were in most biopsies/autopsies where MOG antibodies were present. And their pathology was in multiple sclerosis type II pathology, which points to the direction of antibody-mediated pathology. So from a neuropathological point of view, looks like MS. If you look at the clinical criteria that are currently valid for multiple sclerosis, it's clearly not MS.

If you look at the pathogenesis, this is currently under investigation. From the in vitro studies, we know that these antibodies can, of course, activate compliment. They also have an affect on oligodendrocyte cell function. In vivo models are currently ongoing, and I expect there to be more results by next year on this.

MSDF

What is the clinical utility at this point? Is it ready for clinical use, or what more needs to be done?

Dr. Reindl

I think particular people working in the pediatric field are using it more and more. Because if you look, for an example, at ADEM, earlier this year we published a study that children with ADEM that are positive for MOG antibodies they have certain features in neuroradiology but also in their clinical presentation and their clinical recovery, which could aid the clinician. In particular, in the European countries, many laboratories are now setting up assays for MOG antibodies and using it in clinical routine. What has to be done now is better development of the assay, a comparison of the assays like it has been done for aquaporin-4 antibodies, like international validation experiments. We're currently setting up such an experiment for next year, together with the people in Oxford and other centers. But, my expectation would be that this antibody would have a similar use like aquaporin-4 antibody has. Also, aquaporin-4 antibodies are more specific for a specific type of disease.

MSDF

You've discussed anti-MOG antibodies in terms of diagnosis. You mentioned prognosis, better course. Can they be useful for following therapy? Do the antibodies actually disappear with immunosuppression, or are they always present?

Dr. Reindl

The point is in the monophasic cases the antibodies disappear anyway. So, I guess in 70% to 80% of all patients – particular the pediatric patients – they have these antibodies at disease onset at high titers, and with time they disappear. They only are persistent if there is a bad recovery or if there's a recurrent disease cause, like recurrent optic neuritis would be an excellent example for this. If you look at therapies, of course, therapies like plasma exchange or corticosteroid used at high doses will lead to a disappearance or a drop of antibody titers. I think we have no really long-term experience, at the moment, because these antibodies were just discovered a few years ago, until long-term studies are ongoing.

MSDF

Is there any work on what triggers these antibodies; whether there's exposure of antigens, what agents may be involved—environmental, genetic, viral?

Dr. Reindl

This is the $100 million question. Of course, we would be happy to know it. It's the similar situation like with aquaporin-4 antibodies. Also there we still don't know it. What is particular interesting is that this is most frequently observed in children at the age under 10 years. These are children that are frequently exposed to infections – the respiratory infections and other infection – therefore it's highly likely that the underlying cause is infectious. But at the moment, as far as I know, there were a couple of studies, at least, but no real systematic study using a lot of patients and with a good epidemiological setup.

MSDF

If there's an infectious agent, is it that it is causing damage to myelin, which is exposing antigens, or there's some crossreactivity with the infecting agent itself?

Dr. Reindl

Both things I think could be possible. The animal models tell us a lot of this. This is work published by Hartmut Wekerle’s group three years ago where they discovered that in transgenic animals – animals that are transgenic for MOG T cells – gut bacteria activate these T cells that go into the brain, and then MOG is released, transported out by dendritic cells to the cervical lymph nodes. And at this stage, the antibodies are induced and built. So it's a rather secondary phenomenon, which is caused by T-cell damage and T-cell destruction. I could imagine that a similar phenomenon could also help in the human situation, particularly if you consider ADEM, which has large lesions, a lot of inflammation going on there. I think it's highly likely that antigen is released, and MOG is one of the most antigenic components of the central nervous system.

MSDF

So what are the big lines of research right now – two or three of them – or the big questions that people are approaching?

Dr. Reindl

At the moment, of course, a better developmental definition of the assay—I guess this is one of the most important—is we're working together – a lot of laboratories, a couple of groups – to improve our assays to come to a common standard and to develop an assay which could be used by different laboratories in the world.

The second is, of course, to better define the clinical and neuropathological diagnosis of the patients presenting with these antibodies. Because at the moment, it's rather diffuse. You have children with ADEM, you have children with optic neuritis, children with myelitis. You have adults with NMO-like symptoms. And to put this together in a better way is, of course, highly challenging, and this is work ongoing at the moment. I think we will have more results of this by the next year.

And of course, the third thing is just to look better at the long-term prognosis of these patients. How these antibodies fits in their long-term prognosis, if they are rather beneficial or not. And this is also work that only can be clarified using larger cohorts of patients and international studies.

MSDF

So is it fairly rare to find anti-MOG antibodies?

Dr. Reindl

In adults, yes. In children, no. So if you look at children presenting with demyelinating syndromes, from our own ongoing study cohort in Germany and Austria—we know it's about a third of all children presenting with demyelinating syndromes—more than a third have these antibodies. If you look at adults, it's much more rare. I guess it's about 5% or less.

MSDF

Well, thank you very much.

Dr. Reindl

You're most welcome.

[transition music]

MSDF

Thank you for listening to Episode Seventy-four of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Carol Cruzan Morton. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is vice president of scientific operations.

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

For Multiple Sclerosis Discovery, I'm Dan Keller.

[outro music]

Full Transcript:

[intro music]

Host – Dan Keller

Hello, and welcome to Episode Seventy-three of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller.

Today's interview features Donna Osterhout, a cell biologist at Upstate Medical University in Syracuse, New York, USA. Dr. Osterhout talks about a new way of looking at myelin-making cells, which move and change shape in dramatic ways. Current MS drugs take aim at preventing new immune damage. In the future, researchers hope to figure out how to repair myelin and restore function.

But first, let’s look at new content on MS Discovery Forum. Spring brings rain, flowers, and a bouquet of scientific meetings related to multiple sclerosis. See the list at msdiscovery.org under the tab “professional resources.” MSDF sent the only journalist to cover the recent meeting of the American Society of Neurochemistry in Denver, but you can count on a blitz of news from the media pack at the next meeting on the calendar – the American Academy of Neurology in April, happening this year in Vancouver, BC, Canada. The number of research papers about multiple sclerosis has doubled in the last 10 years, and many findings are first reported at meetings before publication.

Moving on, let’s sample a few of the new papers we found in our weekly PubMed search of the world’s largest medical library, the National Library of Medicine. You can link to each week’s list of curated papers at msdiscovery.org.

Related to this week’s podcast, a new paper reviews the latest research about the molecular cues that allow precursor cells to mature and go through the stages of making myelin. These cues come from axons and from other surrounding tissue. Clinical drug development efforts focus on overcoming inhibitory cues, such as with the experimental agent anti-LINGO-1, now completing phase 2 clinical trials for MS and acute optic neuritis by Biogen. The review authors suggest future drugs to repair myelin could boost permissive and promotional cues, which may go wrong in disease. The paper is published by researchers at the Virginia Commonwealth School of Medicine in the journal Experimental Neurology.

Another report updates the Cochrane systematic review on teriflunomide, a daily oral medication for relapsing remitting MS marketed under the brand name Aubagio by Sanofi Genzyme. Cochrane’s systematic reviews are ranked among the highest level of medical evidence, because of the rigorous independent analysis of multiple studies, including randomized controlled trials. The authors write that, as a single drug, the high dose of teriflunomide was as effective as interferon beta 1-a, while the low dose was less effective. They recommended longer follow-up analyses and noted that the available evidence was low-quality, as well as subject to bias, in part because all studies were sponsored by pharmaceutical companies. In general, side effects were mild to moderate and do not usually lead to treatment being stopped, but the higher dose is more prone to cause these side effects. The study is available in the Cochrane Library.

The final editor’s pick this week takes a fresh look at how medical images transform a patient’s view of her own body. The paper describes an artistic collaboration between Devan Stahl, a bioethicist at Michigan State University with multiple sclerosis, and her sister Darian Goldin Stahl, a printmaker. The resulting art – some of it life sized – superimposes Devan’s narrative and MRI images with body photos. Devan wrote in the paper that the art collaboration has made it easier to talk about her MS. The paper is published in the journalMedical Humanities. If you're in town for the big Neurology meeting, you can catch Darian’s artist talk on April 17 at 2 pm at Malaspina Printmakers in Vancouver, Canada.

[transition music]

And now to our interview. We caught up with Donna Osterhout in Denver, Colorado at the March meeting of the American Society for Neurochemistry. She organized a symposium that told a new story about myelin-making cells. In different labs, researchers started looking for clues in the radical shape changes that occur in the cells in their normal process of making myelin. These oligodendrocyte precursor cells sprout “arms” to reach out and touch neighboring axons. Then they push out slabs of fatty membrane and wrap them around and anchor them to the axons. In multiple sclerosis and other demyelinating diseases, the immune system attacks this myelin wrap, and the cells cannot keep up with repair. The unprotected axons may be damaged or destroyed, causing the worsening disability of MS. Learning how the cells make myelin may pave the way toward new therapeutic agents to repair demyelinated axons and restore function. Dr. Osterhout spoke with our executive editor, Carol Cruzan Morton.

Interviewer – Carol Cruzan Morton

So we are here, in Denver, at the annual meeting of the American Society for Neurochemistry, and you've put together a very interesting panel on a new way of looking at myelin. So can you sort of set the scene for us when you're talking about the myelin research that you're working on?

Interviewee – Donna Osterhout

Well, myelin is a specialized membrane that is wrapped around axons; it occurs in the last step of development. And oligodendrocyte progenitor cells are the cells that form myelin. They are going to migrate out through the developing brain and they're going to extend processes that come in contact with axons that need to be myelinated. And when they get the appropriate signals, they are going to start a process by which they synthesize and extend a large membrane, which wraps around this axon many times and compacts and forms myelin.

The way that this happens has been a mystery thus far, but recent research suggests that there has to be a lot of rearrangements of the internal cytoskeleton for this to happen. And so the symposium was organized to talk about how the cytoskeleton might be changing to allow for this membrane wrapping and myelin formation.

MSDF

Can you tell me more about the cytoskeleton?

Dr. Osterhout

The cytoskeleton is comprised of specialized proteins within cells, and every cell has a cytoskeleton; it gives it shape, but it also allows it to migrate, differentiate, and extend processes, so cells wouldn't be able to do much without a cytoskeleton. And in the case of oligodendrocytes, there are a lot of cytoskeletal rearrangements that occur to allow for myelination.

MSDF

Can you tell me more about the emerging view about how myelination may be working based on this new way of looking at it?

Dr. Osterhout

Initially, we know that there are early signals that trigger extensive process outgrowth from these cells. Once the axon sends a signal to the oligodendrocyte progenitor cell, they start to put out many, many processes, synthesize myelin proteins, and make this big membrane that will wrap around the axon. What winds up happening is that in the past everybody thinks that we've needed a driving force so that something pushes this forward, and it had been thought that perhaps the actin cytoskeleton was the driving force behind this.

The newer research indicates that initially you have to have signals that trigger the process outgrowth, but this is followed by an actual disassembly of the actin cytoskeleton. So it's somewhat opposite of what we had thought previously.

MSDF

Can you tell me more about the steps that are involved in the process of myelinating that you and your colleagues have been discovering?

Dr. Osterhout

Well, the initial step is the activation of a cellular kinase called Fyn tyrosine kinase; this is the earliest step in the differentiation of these progenitor cells. Fyn will be activated by any number of signals from the axon including, for example, glutamate that's released. And once Fyn is active, it initiates a rearrangement of cytoskeletal proteins called microtubules in order to facilitate process outgrowth so we can extend processes to form this membrane.

In later stages, then we have Fyn helping to trigger the synthesis of myelin proteins, and then you start to get other proteins active that will disassemble the actin cytoskeleton. There is even some evidence that perhaps myelin basic protein can do this. So Fyn signaling will turn on early and promote the synthesis of myelin basic protein, and then myelin basic protein will proceed down these processes and help to disassemble the actin cytoskeleton so the membrane can wrap around the axon.

MSDF

Can you describe what the cells look like when they're going through this process?

Dr. Osterhout

Well, this is really interesting to study, especiallyin vitro. You can set up myelinating cultures of oligodendrocyte progenitor cells. They're very simple cells, they're like bipolar, two to three processes, and that's the earliest progenitor that we might look at. But once you trigger differentiation, they start to put out processes in a somewhat predictable manner. They will first extend five processes, and then these five processes start branching And they produce these intricate branches. At some point these mature cells will actually look like a lace doily; they are spectacular with the cell body in the center and all these highly branched processes surrounding it. And then you see a transformation of these processes into this huge membrane sheet, and in the absence of an axon it's just going to cover the tissue culture dish; it's amazing how large this can get. But if you had an axon in the culture, this membrane sheet would just form myelin. They would form a myelin segment wrapping around the axon.

MSDF

That’s so interesting. And then can you say, adding to that picture, the steps that are happening in those process that you and your colleagues have been discovering?

Dr. Osterhout

So when you have the initial process outgrowth, you have Fyn tyrosine kinase active, and that facilitates the initiation and that extensive process outgrowth. But the transition between the process outgrowth and the formation of membrane sheets is going to be the disassembly of the actin cytoskeleton.

MSDF

And that's the big news is that the actin cytoskeleton is breaking down instead of pushing the myelin forward as it's making its multiple wraps around?

Dr. Osterhout

Yes, this seems to be the way that this is happening mechanistically. The formation of that myelin membrane requires the actin disassembly, and two of the speakers that we had in our symposium gave evidence to this, using several different experimental systems. And then ultimately when you're going to anchor this myelin sheath, and you can get some specializations in the axonal membrane, and this is what one of the speakers talked about, anchoring the perinodal loops, kind of the ends of the myelin segment. And so we have a process by which we have extensive process outgrowth triggered by Fyn. Then once you get the process outgrowth, you have actin disassembly and you form these membrane sheets, and then they would wrap around the axon, forming myelin, and then you would stabilize it with special proteins in the axon that stabilize the ends at the perinodal loops.

MSDF

So what does this have to do with diseases like multiple sclerosis?

Dr. Osterhout

That's a very good question. If we understand what goes on in development, then we might be able to predict how we could facilitate this process in a demyelinating disease like multiple sclerosis. We do have oligodendrocyte progenitor cells in our brain and spinal cord. They persist as a population throughout adulthood. And any time you have a lesion or a trauma to the brain, and especially if you get demyelination, then you'll have these cells migrate to the area of demyelination. And if we can encourage them to remyelinate, they would undergo the same steps.

We have shown evidence that the inflammation and other conditions in a demyelinating disease upregulates chondroitin sulfate proteoglycans, and these can actually inhibit the process outgrowth and remyelination by oligodendrocytes, because they ultimately inhibit the activation of Fyn kinase.

So if you're considering a disease process, you want to stimulate these steps. And you want to look for agents that might trigger and make sure that these steps proceed, or neutralize things that would be present in the lesion that would inhibit this.

MSDF

One interesting aspect of your work, and perhaps of science more generally, is that some of these discoveries with relevance to multiple sclerosis come from your work on spinal cord injury. Can you talk about how that works in science?

Dr. Osterhout

Well, spinal cord injury is another type of lesion, it's a specialized lesion; you have damage to axons as well as demyelination due to trauma. But in diseases in general in the brain and the spinal cord, whenever you have an injury process or inflammation or some kind of destruction of tissue, you get an inflammation and immune influx, and you will get a process called reactive gliosis. And this is common to many diseases that you see in the brain. For example, you can see it easily in spinal cord injury, it's been well documented. You can see these proteoglycans' reactive gliosis in multiple sclerosis, you can see it in Alzheimer's disease, Parkinson's disease, and other conditions, because they all have a common element that you've got some kind of inflammation occurring and tissue destruction occurring at a specific place.

MSDF

Getting back to multiple sclerosis and the work on how cells myelinate axons, what are the next big questions that you and your colleagues are asking?

Dr. Osterhout

Well, there still are a lot of questions about exactly how this myelination process is accomplished even during development; we don't fully understand all of the triggers that would activate this process. And, likewise, we don't always understand things that might inhibit this process. So we need to more fully characterize what's going on in development so that we can take a look at it in the remyelinating situations, either in spinal cord injury, or multiple sclerosis, or any other demyelinating condition.

MSDF

Well, that's really interesting. Well, thank you for taking the time to explain the research.

Dr. Osterhout

And thank you for your interest; it's been my pleasure.

[transition music]

MSDF

Thank you for listening to Episode Seventy-three of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Carol Cruzan Morton. Msdiscovery.org is part of the nonprofit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is Vice President of Scientific Operations.

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

[outro music]

Transcript:

[intro music]

Host — Dan Keller

Hello, and welcome to Episode Seventy-two of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller.

Today's interview features Nathaniel Lizak, a young Australian investigator from the University of Melbourne who gave the first talk at the recent meeting in New Orleans of the Americas Committee for Treatment and Research in Multiple Sclerosis, or ACTRIMS. Mr. Lizak discusses new findings showing that moderately advanced and advanced multiple sclerosis are more unpredictable than anyone knew, but worsening disability may be slowed by highly effective therapies.

But first, let’s look at new content on Msdiscovery.org.

Our latest data visualization shows statistical snapshots of MS worldwide. Survey data from the MS International Federation show that, as of 2013, the estimated number of people in the world with MS increased to 2.3 million, or about 33 people with MS for every 100,000 people. But MS rates and access to care vary widely from country to country, as you can see from the data visualization.

In a new job posting, the Stanford-affiliated Santa Clara Valley Medical Center Department of Neurology seeks a general neurologist. Subspecialty training in MS, movement disorders, or vascular neurology is preferred. You can post your job at MSDF at no charge to reach researchers and clinicians specializing in MS and related demyelinating disorders.

[transition music]

And now to our interview. Australian medical student, Nathaniel Lizak, and his academic mentors took a second look at how disease progresses in people with moderate and advanced MS and what can be done about it. Researchers are looking for better measures of disability, but the most common one is the Expanded Disability Status Scale or EDSS for short. Lizak and colleagues looked at worsening disease from several starting points, using an international registry known as MSBase that tracks medical record data on nearly 38,000 people with MS. They divided people in three epochs ranging from EDSS 3.0 (where people are moderately disabled but are fully ambulatory) to EDSS 6.0 and higher (where people need assistance to walk short distances). An older study suggested a steady worsening of disease after EDSS 3.0, which Lizak and co-workers questioned. Executive editor, Carol Cruzan Morton, spoke with him about their findings.

Interviewer – Carol Cruzan Morton

We are here at the ACTRIMS meeting in New Orleans, and you opened the conference with a really interesting paper. I wanted you to explain a little bit about what you were asking and why. What area of MS, what questions you are addressing?

Interviewee – Nathaniel Lizak

So we did this work under the MSBase group, which is an MS-based cohorts; it is an international really large study that has data from over 30,000 patients worldwide. We have access to all of their data, and we really thank our contributors throughout the world who have provided this.

We decided – because we have so much power with so many numbers and so much data from patients – to look at the latest stages of multiple sclerosis which, so far, haven't really been that well explored.

There have been three studies in the past which looked at disability and how it progresses in what they have called the moderately advanced stage of multiple sclerosis. So yeah, we looked at disability accumulation in the later stage of multiple sclerosis moderately advanced, which is defined before as between the EDSS steps of 3.0 or 4.0 and 6.0, and we wanted to look at what predicts how the disability accumulates, because a lot of the previous studies didn't really suggest anything really changes disability.

There is this notion amongst doctors that once it hits these thresholds the trajectory is set, and there is nothing you can do to help patients. We didn't believe that. We were hoping there was something you can still do for patients, even once they have already accumulated substantial amounts of disability.

We set this up to look at just how much variability there is in these later stages of disease and what we can do to take it from going really fast to going really slow, to preventing patients from getting even worse.

We used our cohorts, ran lots of statistics, and we found some very interesting results. The first is that this late stage of disease is quite independent from what happens before. How many relapses people have early in the disease, how fast they got to the early disability landmarks, how fast they accumulated disability, if they were on therapy in the past—all of those things don't really seem to impact what happens later on in the disease. That is what we call the amnesic disease phenomenon. That is something that has already been explored in the past. We kind of confirmed that and saw that, that happens at lots of stages in multiple sclerosis.

What is more interesting, though, is that we still found that patients have a lot of variability in what happens to them, even after they have accumulated substantial disability. So in technical terms, after EDSS 3.0, 4.0, and 6.0, there is still a lot of variability in what happens to patients after they have reached these steps, after they have already obtained disability. That suggestion that after the threshold the disease is set doesn't seem to be at all the case. That is all we observed in our patients.

We had over 3,400 patients— we had 3,415 patients exactly. So it is quite I think, generalizable, our results. There is a lot of variation in what will happen at these later stages of disease.

MSDF

You can't predict what happens next. And it is different.

Mr. Lizak

It is different for everyone. It is independent of what happened before, and almost nothing predicts what is going to happen next. The only things that we found which did predict such as how does disability progress in these later stages, the first one was how many relapses they are having now. Not before, not early in the disease, but how many relapses are they now having per year at these later stages?

We found that more relapses later in the disease still contribute to disability. That wasn't something that the other studies had actually shown, and I think that is to do with their methodology more than anything else. I think we are confirming that relapses are still important, inflammation is still important, we still need to treat it, no matter how far along the disability line the patients are. The relapse is still a problem.

A more exciting thing that we found was that the immunomodulatory medications that the disease modifying therapies, the higher efficacies ones, the new medications, the longer patients are on those in the later stages of disease—so again, after those landmarks, after EDSS 3.0, 4.0, and 6.0—he longer patients are on those after they have gone into that disability the lower their likelihood of progressing even further to EDSS 6.0 and 6.5, which is mobility issues needing unilateral assistance or a walking stick, EDSS 6.0 or bilateral walking assistance EDSS 6.5. So those are pretty, obviously, important to patients in being able to move around without needing any aid.

We found that we can prevent patients from getting to these later disability stages with longer time on disease therapies later on in the disease. So the conclusion we got from this is patients should continue being treated later in multiple sclerosis. Of course, it's always a risk/benefit calculation. You always need to take the side effects into consideration and look at the patient that you are seeing. It is not a blanket rule, but there are countries in the world where it's by policy you can't give therapies later on in disease after EDSS 4.0.

New Zealand is one example. In other places in the world, it is just practice to stop giving treatments later in multiple sclerosis, and we are suggesting no there still is a benefit and you should be weighing that up when considering whether or not to continue patients on therapy, whether to start them on stronger therapies. There is evidence that we can still slow down how the disability will accumulate. That was our main message. We were a bit surprised to find out it was not what we were expecting, but we are very happy that we found such results.

MSDF

In your study, what drugs were categories as the high efficacy?

Mr. Lizak

I don't remember exactly every single drug, but we just put into two groups. The low efficacy being primarily the initial very first-line drugs, so interferon, glatiramer acetate, and teriflunomide; everything else categorizes as high-efficacy therapy, so natalizumab, fingolimod, alemtuzumab, dimethyl fumarate, cladribine, mitoxantrone, I might be missing a few. By no means are we saying that one therapy is better than another. We're just looking at the class effect of the really strong medications. We don't yet have the power to say this is the best medication after EDSS 6.0, this is the best medication after EDSS 4.0, or don't go on that one. We're just trying to say that the stronger perhaps second-line therapies often used second-line do have a better effect in this later period of disease, and doctors should be considering that when deciding what treatments their patients should go on, and patients should obviously be made aware of that as well.

MSDF

The idea that things that happen before don't affect the later stages seems on the surface to be at odds with the idea that progressive disease starts early, like treat early.

Mr. Lizak

…to try to treat disease as early as possible. I don't think it is at odds. There's been a lot of work, so far, to say that the earlier you treat your patients the better. We agree with all of that. We are not saying treating later is any better. Probably believe that treating earlier is better, but what we are saying is: a) continue treating, and don't stop treating. I completely agree that all of the patients that we found that after EDSS 3.0, 4.0, and 6.0 improved with more therapy after those landmarks, still probably did better earlier on in their phase of disease with therapy then. But I guess what we saw is the therapy they had earlier in disease won't make an impact now. You need to continue treating these patients for them to have an improvement.

We still absolutely encourage the earlier treatment, the better. That evidence is beyond doubt in multiple sclerosis. We are definitely not challenging that. We completely agree with that. Our evidence just goes and takes it one step further of, the earlier the better, but it is not too late.

MSDF

Now you are doing this study in the context of a clinical practice. How has that changed – or has it changed – how people with MS are treated in the decision making?

Mr. Lizak

The thing is, first of all, I am a medical student, so I don't make any of the decisions. Secondly, where we are based in Melbourne, Australia, there is already a tendency to treat patients later on in disease. Obviously we haven't published the results yet, so we haven't seen how much of an affect it will have worldwide. Perhaps now we will begin to start changing things. But in Australia where nothing was studied, no one was surprised to find that this was the case. All the doctors there already treat their patients later on in the disease. So it just confirmed that what they are doing is correct. No one has yet drastically changed how they are treating patients. We hope though that, say countries like New Zealand whereby policy after a certain EDSS score, after EDSS 4.0, after moderate disability has been accumulated, you can't put patients on disease-modifying therapy anymore—we hope that is where we will have the biggest impact.

MDSF

When you gave your talk, you talked about the earlier study. There wasn’t an appreciation for the variability. How did you come to ask that question in the first place?

Mr. Lizak

I have to give credit to my supervisor, as well as the whole MS based team that was behind this study, and obviously they conceptualized it a lot more than I: Dr. Thomas Kalincik and Helmut Butzkueven, in particular. But a lot of doctors, particularly our team, are not happy with that graph. Which it looks like everyone after EDSS 3.0 has the same trajectory. We looked at this, and we thought we wanted to do a study to prove this wrong. We didn't know exactly what we were going to find. We actually proved that what they first suggested of disease being independent to be quite correct. But they just missed the variance in the second half. It is independent, but it is still really variable.

We looked at the graphs carefully, and we looked at the study carefully, and we made the note of they only have a mean value on that top half, they don't show how much variability there may or may not be in disease. We got confused. We said it is unlikely that patients have no variability at all after EDSS 3.0, and we decided not only are we going to look at what predicts the later disease, but we need to know just how variable is this disease this late, and we found that it is extremely variable. After EDSS 6.0, patients might go straight through to worse disability, and many will improve, and many will stay stable for many years. We were just unhappy with the message that the graph gave. Then we tried to scrutinize exactly where can we change this message, where can we improve this.

MDSF

That’s great. What questions are your colleagues asking you here about the study?

Mr. Lizak

I have had a lot of questions about this study, some more helpful than others. A lot of people have asked how will this change management? And I think we have just spoken a little bit about that. I am asked, as well, how do you tell patients that we can no longer predict their disease? We used to think that we could and now we just outright can't predict their disease and that is something that is going to be difficult to tell the patients. I think you need to frame it differently. It is not we can't predict how your disease is going to go, it is, we have hope for making it better. You might have been doing not so well up until now, but we still have hope to continue fighting. We haven't given up yet. And I think that is what we need to be framing it as. That is one of the questions I have gotten the most.

A lot of people have asked about why we chose certain therapies, and there is very little evidence about which therapy is high and which therapy is low. We just used the available studies as well as the clinical experience and just compared how much they reduced relapse rates and so on. It was partly based on intuition and observation. It could be the case that some therapies should have been classified differently to what we did, but it is very hard to tell at this stage.

Even then, even looking at the list, you should be mindful that a therapy that we classified as high efficacy might have actually been bringing that group down. And maybe should have been a low efficacy therapy, and maybe a low efficacy therapy was the only one working in that group, and it should have been in the high efficacy group. So obviously, be very careful when you look at that.

At that strata, it is not meant to be telling anyone I should be on that drug or I shouldn't be on that drug. It is just meant to be saying that strong medications are better in this stage, but the decision of the medication should be a decision made entirely by the patient and their doctor, and it should only be used to influence and it shouldn't be taken any more than that.

MDSF

Is rituximab in your …. I was going to say before a B cell therapy.

Mr. Lizak

I don't think we have many patients on rituximab, but we would have had quite a few. Yes, because it was used quite extensively.

MDSF

Thanks. Is there anything else that I haven't asked or that you wanted to add?

Mr. Lizak

Rituximab wasn't the high efficacy group. I should mention that. Yes. Thank you for the fantastic opportunity to showcase the work we have been doing. I obviously have to give credit to everyone at MSBase who conceptualized and gave patients the study. We couldn't have done it without the help of our collaborators worldwide.

[transition music]

MSDF

Thank you for listening to Episode Seventy-two of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Carol Cruzan Morton. The data visualization was developed by Jean Mercier of Khawai Data Visualization at Khawai.com. Msdiscovery.org is part of the nonprofit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is Vice President of Scientific Operations.

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

[outro music]

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

For Multiple Sclerosis Discovery, I'm Dan Keller.

Transcript to come soon

[intro music]

Host – Dan Keller

Hello, and welcome to Episode Seventy of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller.

In today's interview, we'll talk with Dr. Brian Weinshenker of the Mayo Clinic about new diagnostic criteria for neuromyelitis optica spectrum disorder and how it differs from MS. The new criteria build upon and broaden the definition of NMO that was based, in part, on the presence of antibodies to aquaporin-4.

But to begin, let’s sample a few of the new studies we found in our weekly PubMed search of the world’s largest medical library, the National Library of Medicine. You can link to each week’s list of curated papers at msdiscovery.org.

On topic with our interview, an international team led by researchers in Tianjin, China, found a unique group of people with neuromyelitis optica spectrum disorder, or NMOSD, who carried autoantibodies to both aquaporin-4 and myelin oligodendrocyte glycoprotein or MOG, a minor component of myelin. Among the 125 patients, 10 were double positive for both sets of antibodies, and 14 were positive only for MOG. The double-positive patients had a worse disease course, most having MS-like brain lesions and more disability. Those with only MOG antibodies had a milder disease and less disability. If verified in other studies, the findings may help predict the clinical course of NMOSD or even define a new phenotype somewhere between the two very different diseases of NMOSD and MS. The authors say their paper also raises a new challenge of how to diagnose and treat such patients. Three double-negative patients did not respond to rituximab, a highly effective anti-B cell therapy used off label for MS and NMO. The study is published in the journal Science China Life Sciences.

For people with MS and other demyelinating conditions, bladder issues can play an oversized role in the quality of life. A pair of review articles addresses the “neurogenic bladder.” One from Duke University researchers in North Carolina, USA, recommend an evaluation known as urodynamics, calling it the gold standard in helping to break down the complex problem into basic and treatable factors. In the other paper, researchers from Western University in Ontario, Canada, review the 16 different ways to measure patient reported outcomes for neurogenic bladder, and how to choose the best one to track patients’ quality of life. Both reviews are published in the journal Translational Andrology and Urology.

In the news section, MS Discovery Forum correspondent Stephani Sutherland wrote about the recent negative results of fingolimod in a large Phase 3 clinical trial of people with primary progressive MS. Even in failure, studies can be informative and can help researchers design better investigations to test potential therapeutics for progressive disease.

Now, let’s move on to our drug development database. The drugs with important additions and changes are daclizumab, fingolimod, and ocrelizumab. One update reflects findings presented at last month’s ECTRIMS conference in New Orleans suggesting that in primary progressive MS, the experimental drug ocrelizumab reduces disease activity in subgroups of individuals with and without gadolinium-enhancing images at baseline.

[transition music]

And now to our interview. It’s been 11 years since neuromyelitis optica, or NMO, was redefined as a separate disease from MS. Thanks to the discovery of the first biomarker for NMO, an antibody against aquaporin-4, diagnostic criteria for neuromyelitis optica, or NMO, were revised. In today's discussion, Dr. Brian Weinshenker of the Mayo Clinic in Rochester, Minnesota, USA, lays out further revisions to the criteria and the reasons for them. He uses a couple of terms that may warrant definition. One is IgG, which is immunoglobulin G, a particular class of antibody. Other terms are seropositive, meaning, in this case, the presence of antibodies to aquaporin-4, and conversely, seronegative, the absence of such antibodies. Finally, ADEM, A-D-E-M, is acute disseminated encephalomyelitis, a sudden, widespread attack of inflammation in the brain and spinal cord, usually seen in children. I spoke with Dr. Weinshenker at the ECTRIMS meeting last fall in Barcelona about the new consensus diagnostic criteria for NMO.

Interviewer – Dan Keller

Is there something that was lacking before?

Interviewee – Brian Weinshenker

Well, the first diagnostic criteria for neuromyelitis optica were proposed by our group at Mayo Clinic in 1999. And in 2006, with the advent of the first diagnostic biomarker for neuromyelitis optica, an antibody which we now know is directed against aquaporin-4 – I’ll call it aquaporin-4 IgG – the criteria were revised. But there was a need to revise them. We became increasingly confident in this diagnostic biomarker, and it was possible to make an earlier diagnosis, often after the very first symptom. So that was one key driving factor.

And furthermore, with the advent of this biomarker, we’ve appreciated that the spectrum of this disease is far broader than we had previously recognized. And there are a number of clinical syndromes that were previously not recognized as being part of the neuromyelitis optica spectrum that we now know are, and those needed to be integrated. Another key factor was the fact that a number patients that we recognize have this same condition now did not meet the old criteria. For example, you had to have both optic neuritis and myelitis to make this diagnosis, and we recognize some patients with this condition have just recurrent myelitis or just recurrent optic neuritis; they wouldn’t have satisfied the criteria. So those were the key reasons that drove developing new criteria.

MSDF

What are some of the new criteria?

Dr. Weinshenker

The first important point is that we’ve eliminated distinction between neuromyelitis optica – that is, having optic neuritis and myelitis – and having some of these more limited forms or unusual forms of the disease with brain lesions. And we’ve used the term neuromyelitis optica spectrum disorder to refer to all of them.

Second aspect of the diagnostic criteria is that we’ve stratified them based on whether or not you have this biomarker, the aquaporin-4 IgG. And we’ve separately defined patients with that biomarker and those without, the largest group being those with the biomarker. So in the patients with this biomarker, we really require only one clinical syndrome. The clinical criteria are very, very liberal, and we don’t even require, say, for myelitis, as we had before, we used to require having a long spinal cord lesion. We now recognize that about 10 to 20% of patients do not have those kind of long spinal cord lesions when they have a myelitis, so we no longer require it if you have that biomarker.

But we’ve left open a category that we call seronegative neuromyelitis optica spectrum disorder, because some patients who meet all of the various clinical criteria’s, even the strictest clinical criteria, seem to be seronegative for this biomarker. We recognize that’s a heterogeneous group of patients; some of them ultimately will become seropositive. In some of those patients, we’re recognizing other antibodies that seem to be associated with a similar clinical syndrome, so I think, ultimately, we may create new silos based on those biomarkers, but when these criteria were developed, it was felt to be premature to include other antibodies as diagnostic biomarkers. So we’ve grouped them into this group of seronegative NMO spectrum disorder.

But we’re much more strict in that category. We do require two clinical syndromes – two different clinical syndromes – and in some situations we do require additional MRI criteria in order to meet those criteria.

MSDF

Okay, because it was sounding like you were being so liberal about it people could lack this symptom and that symptom and antibody, but, in this case, if they’re lacking antibody, they need other criteria to qualify.

Dr. Weinshenker

That’s correct; both clinical and radiologic criteria. And we also have exclusionary – well, I shouldn’t say exclusionary. There are no exclusionary criteria. We refer to them as red flags. If you have certain characteristics that would make it more likely that you have MS, which is the major competing diagnosis, or if you have certain comorbidities like, say, cancer or sarcoidosis – we know sarcoidosis can sometimes mimic neuromyelitis optica – we add that as a note of caution, but strictly, no criteria is considered exclusionary for a diagnosis of neuromyelitis optica spectrum disorder.

MSDF

Would other systemic autoimmune states also fall into the category of red flags: we’re going to have to decide whether it really is NMO or not?

Dr. Weinshenker

Actually, that used to be excluded by some people that if patients had systemic lupus or Sjögren's disease they were excluded, but we recognize that patients with neuromyelitis optica spectrum disorder have an excess of those other autoimmune diseases. We very frequently detect comorbid disease, so we actually say that, say, a diagnosis of lupus or Sjögren's actually increases the chances that his patient has neuromyelitis optica spectrum disorder if they present, say, with optic neuritis or myelitis. The old literature was replete with patients who were described as having lupus myelitis. Actually the majority of those patients actually have comorbid neuromyelitis optica spectrum disorder. So it’s no longer an exclusionary criterion.

MSDF

There used to be a requirement for bilateral optic nerve involvement? Is that right? Has that gone by the wayside?

Dr. Weinshenker

Yes, this is before there were actually formal criteria, but yes, that was considered to be, say, a red flag that you might be dealing with neuromyelitis optica compared to standard MS. We recognize that that applies to a relatively small percentage of patients, so it doesn’t really appear in these current diagnostic criteria, but certainly it would not exclude it. And I would say that it does add to the suspicion that someone has neuromyelitis optica spectrum disorder compared to MS.

MSDF

What about pediatric neuromyelitis optica spectrum disorder?

Dr. Weinshenker

We did have several people, who were pediatrics experts, on our international panel and, in general, it was felt that the same criteria that we’ve applied to adults can be applied to children. We do recognize that certain brain syndromes are relatively more common in children, and there is one caveat, that is, in pediatric multiple sclerosis, sometimes patients will have long spinal cord lesions, and that’s one of the criteria that adds to the suspicion that somebody has NMO spectrum disorder as to MS. It may be somewhat less reliable in children.

MSDF

Is there any confounding or concern about ADEM in children?

Dr. Weinshenker

Well, neuromyelitis optica spectrum disorder can be associated with brain lesions that can be interpreted as ADEM. They can be large, tumefactive, extensive. Brain biopsy, which is not part of the criteria that we use for neuromyelitis optica spectrum disorder, can sometimes differentiate ADEM – standard ADEM – from the ADEM-like lesions that occur in neuromyelitis optica spectrum disorder, so yes, it can be a diagnostic problem. But generally speaking, if one relies on the other criteria – the presence of optic neuritis and myelitis, which can occur in both ADEM and neuromyelitis optica spectrum disorder – usually one can come to a clinical diagnosis. But there are some situations that can be confusing and occasionally additional tools, even brain biopsy, can be necessary to make a definitive diagnosis.

MSDF

If serologic testing is not available, do you still require the two other criteria to make the diagnosis?

Dr. Weinshenker

We propose that, for now, if serologic testing is not available – and there aren’t many places in the world where it’s strictly unavailable; it is offered worldwide – that you rely on the criteria for the seronegative and satisfy those criteria of seronegative NMO spectrum disorder.

MSDF

Are the criteria fairly straightforward that any neurologist up-to-speed can interpret them and use them clinically?

Dr. Weinshenker

Yes. We have designed these so that they can be used by neurologists in standard practice. Obviously, they don’t cover every single possibility, and there are complex patients where consultation will be necessary, but these are designed to be as good any diagnostic criteria can be. I think one has to realize that diagnostic criteria are for typical patients with conditions, and there are rare situations in difficult-to-interpret situations where one does need this kind of consultation.

MSDF

What about other historical terminology, and what kind of recommendations have you made vis-à-vis that?

Dr. Weinshenker

This has been a confusing element of the literature. For example, one term used in Asia, where it was recognized that you can have a relapsing condition that primarily targets the optic nerves and spinal cord was often referred to as Asian or Japanese opticospinal MS. And historically, this has been a very important contribution. I think our colleagues in Asia were the first to recognize that this relapsing condition was distinct from MS and may be something different, but the terminology was confusing. It was called opticospinal MS. Was this MS or something distinct from MS? And was it the same as neuromyelitis optica?

And the panel felt that this term is no longer useful in clinical practice, and it doesn’t distinguish from multiple sclerosis. So it was felt all of those patients could be probably put into either the NMO spectrum disorder category or multiple sclerosis category, proposed that, for clinical practice, that terminology be eliminated.

MSDF

This is a good way to make the diagnoses, but it leads into the question of then what do you do? And next week’s podcast will focus on new clinical approaches to looking at NMO.

[transition music]

Thank you for listening to Episode Seventy of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Carol Cruzan Morton. Heather McDonald curated the MSDF drug database updates. Msdiscovery.org is part of the nonprofit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is Vice President of Scientific Operations.

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

For Multiple Sclerosis Discovery, I’m Dan Keller.

[outro music]

Transcript will be available soon.

Transcript to come soon

Full Transcript

[intro music]

Host – Dan Keller

Hello, and welcome to Episode Sixty-Seven of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller.

We’ll hear from Neda Razaz, a doctoral candidate at the University of British Columbia in Vancouver, Canada, on her research looking at what it means for child development when a parent has MS. The findings may help parents and health care professionals define strategies and services for children when needed.

 First, let’s check out a few of the 70 new research papers we found in the last week. You cn see each week’s list of curated papers at msdiscovery.org.

There’s a large and confusing cast of players in demyelinating diseases, such as MS and neuromyelitis optica spectrum disorders. But if the central nervous system was a stage set in a spaghetti Western movie, at least everyone knows the bad guys wearing black hats would be the T cells, right? Hold your horses, say the German and U.S. authors of a review paper in the journal Trends in Immunology. New findings in the last year reframe the story. Some T cells wear white hats. In fact, the central nervous system may need T cells to limit opportunistic infection, inflammation, and damage. Some MS drugs may work by redirecting T cell behavior. Side effects of other MS drugs may come from blanket suppression of all T cells.

Now is the time to cue the theme from the movie Jaws. In the history of life on Earth, the kind of myelin that researchers are trying to protect and restore in people with MS and related disorders first showed up in a family of shark-like fish and skates and rays. The first true myelin basic protein seems to have originated in this family of cartilaginous fish, called chondrichthyans, or their ancestors. This information comes from an article in a special issue on myelin evolution in the journal Brain Research.

A third paper that caught our attention looks at modern myelin. Almost every cell in the body has little energy packs called mitochondria. That’s true with brain cells, including the oligodendrocytes that make the myelin membrane that wraps around axons. Researchers from Norway say they have shown, for the first time, mitochondria moving into the myelin wrap. They also report that oligodendrocyte mitochondria are smaller, slower, and move less often than those in astrocytes and neurons.

Now, to our drug development database. The drugs with important updates this week are fingolimod, glatiramer acetate, interferon beta-1a, mitoxantrone, and natalizumab. One update summarizes a press release indicating that a generic version of fingolimod has been launched in Russia.

[transition music]

And now to our interview. The University of British Columbia in Vancouver, Canada, has a strong program in MS. We spoke with several of their researchers at the ECTRIMS meeting in Barcelona last fall. Today Neda Razaz, a PhD candidate, fills us in on her work on the impact of living with a parent with MS on child development or wellbeing

Interviewee – Neda Razaz

I study a group of parents with MS and their children, and we actually use health administrative databases to capture our cohort of interest.

Interviewer – Dan Keller

And what were the outcomes of interest, and how did you assess them?

Razaz

So, for one particular study that was actually published recently, we were interested in child developmental outcome at kindergarten. So I used the Early Child development instrument, which is a routinely collected database by kindergarten teachers in their classroom. And the specific instrument measured children’s wellbeing from social, emotional, and physical wellbeing. And that was our outcome of interest for that particular study.

MSDF

What did you find?

Razaz

I actually found that children who have a parent with MS were doing as well as children without a parental MS, so having a parent with MS was not associated with adverse developmental outcome.

MDSF

Was any aspect of parental mental health associated with children’s outcomes?

Razaz

Actually, yes. In the study, when we did a sensitivity analysis, we found that, in parents who had mental health condition, children were at higher risk of developing some adverse developmental outcomes, specifically in their social and emotional domains of their development.

MSDF

Could you tell if these parental mental health aspects had anything to do with the MS

Razaz

We didn’t specifically look at that, but it is very well-known in the literature that mental health is highly associated with MS. So we kind of feel that it’s not the MS particular; it’s the comorbidities that come with MS that might have an impact on the child.

MSDF

Did it matter whether it was the father or the mother with the issues?

Razaz

We did look at gender specifics, and in one study we did find that having a father with MS who had a coexisting mental health morbidity was also having an impact on child developmental outcome. Specifically for the fathers, it was their emotional wellbeing. But, however, for most of our studies we probably didn’t have enough fathers to be able to see a meaningful difference.

MSDF

Could you get a handle on alcohol use?

Razaz

No, I – we didn’t specifically at that, no.

MSDF

In the case of maternal MS, did it matter whether the disease was present during pregnancy, or if it arose sometime later in childhood development?

Razaz

We didn’t specifically examine the timing of the maternal MS onset, so I can’t comment on that specifically, but our inclusion criteria was that MS had to occur some time before the child reached five years of age. And 60% of our MS cohort had their first onset of MS after their pregnancy

MSDF

Does that give you any clue into the child’s duration of exposure to these issues?

Razaz

We did look at that, and in one study we found that there was a significant association between the duration of the child’s exposure to parental MS and adverse developmental outcome. And I actually feel that’s a very important question, and I’m exploring this further in my future studies as well.

MSDF

Can you put this into context? How does it compare to parental issues in other diseases?

Razaz

Some of our findings are broadly consistent with other chronic illnesses and is actually a specific meta-analysis looking at children who have parents with medical illnesses found that, overall, these children higher rates of internalizing behavior such as anxiety, depression, compared to children who don’t have parents with MS. However, most of these studies, their study population were adolescents, and it’s kind of different from ours kindergarten-aged children. So that might explain some of the differences in the findings that we found. So maybe being that young, at age five, is too early to have any impacts. And also maybe the parents with MS, their disease is not as advanced

MSDF

Are you or someone else going to follow these children as they age?

Razaz

I am interested in actually – you know, my future studies I would like to do a longitudinal study of following these children until older ages; so at least until the time they are 18, and see whether they have a different rates of mental health disorder compared to children who don’t have a parent with MS. I’m interested in, like, specifically living with a parent with a chronic illness.

MSDF

What are the implications of your findings, and can you make any recommendations?

Razaz

While other studies are needed to confirm our findings, we believe that health professional need to be aware of the effect of mental health morbidity that is commonly associated with MS and its impact on their families. And we believe that mental illness such as anxiety and depression among MS patients should suggest the need for appropriate support for their children, because these children seem to be at higher risk of having some adverse developmental outcomes.

MSDF

What have we missed or is important to add?

Razaz

So I just want to say that these studies represent the first important steps in making a difference in MS. We are describing and exploring association, however; we and others in the field need to know if intervention at any way can make a real difference in the lives of parents and their kids.

MSDF

Whom would the intervention involve?

Razaz

The intervention should be family-centered intervention, having the MS patient and also the other parent and other children in the household. So it shouldn’t be individualistic, and it should be the whole family as well.

MSDF

Very good! I appreciate it. Thanks.

Razaz

Thank you very much.

MSDF

Two months after this interview, in late December, the findings were published in the journal Multiple Sclerosis. The paper is free and open to non-subscribers, and you can find a link to it on the podcast page on msdiscovery.org. There you can also find links to be papers and drug development database.

[transition music]

MSDF

Thank you for listening to Episode Sixty-Seven of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Carol Cruzan Morton. Heather McDonald curated the MSDF drug database updates. Msdiscovery.org is part of the nonprofit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is Vice President of Scientific Operations.

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

For Multiple Sclerosis Discovery, I'm Dan Keller.

[outro music]

Transcript will be available soon.

Transcript available soon.

[intro music]

Host – Dan Keller

Hello, and welcome to Episode Sixty-Three of Multiple Sclerosis Discovery, the Podcast of the MS Discovery Forum. I’m Dan Keller.

We’ve just passed the winter solstice. What better time than the shortest daylight hours of the year to check in with research at the University of British Columbia on sunlight and MS? Today we talk with Dr. Helen Tremlett who is exploring sun exposure over a person’s life course and how that syncs with their MS risk and disease course.

In the weekly papers section on the MS Discovery Forum, this week’s list includes nearly 150 newly published research reports that could lead to better understanding and treatment of MS and related disorders.

We selected four papers as editor’s picks. In one paper, researchers think they may have the first experimental evidence that MS may start with damage or loss of myelin-making cells in the brain and spinal cord. In this new mouse model of progressive MS, experimentally damaged brain cells make it hard for the mice to walk. The mice recover when their brain cells repair on their own. Six months later, the MS-like disease returns. In the study, the team showed that nanoparticles targeting the autoimmune reaction prevent the second phase of the disease. The study shows support for an “inside-out” model of MS. That’s different from the “outside-in” model, in which some aspect about the immune system goes wrong and then initiates the attack on myelin-making cells. The paper is published in Nature Neuroscience by collaborating researchers from Northwestern University and the University of Chicago.

To grow and be healthy, all human cells need a signaling molecule named mTOR, named for the mammalian target of rapamycin. That’s true for myelin-making cells, or oligodendrocytes, as listeners may remember from an earlier podcast interview with Dr. Wendy Macklin. The ability to make myelin seems to depend on a key part known as mTOR complex 1, also called its raptor subunit. In a very basic advance, scientists have determined the atomic architecture of the raptor, or mTORC1, piece. The details are reported in the journal Science and provide a structural basis for studying mTORC1 function.

In another editor’s pick, a review of cases of pediatric neuromyelitis optica, or NMO, showed that new international diagnostic guidelines applied well to children. Unfortunately, they also found that children with NMO have delayed treatment and worse short-term outcomes compared to those with MS. The authors urged immediate adoption of the guidelines to select the best treatment and improve outcomes.

In the fourth editor’s pick, researchers found a potential new target to protect axons in a mouse model of neurodegeneration in multiple sclerosis. The target is a pore in the mitochondria, the cellular battery that provides energy. They designed a molecule to block the pore and showed it helped protect neurons and improved the mice’s mobility, all with minimal immunosuppression. The paper by mostly UK researchers is published in the Journal of Biological Chemistry.

Now, let’s take a look at the latest Drug Development Pipeline updates. The drugs with important additions and changes are dimethyl fumarate, fingolimod, glatiramer acetate, natalizumab, and rituximab. One update reflects findings from post-hoc analysis of clinical trial data showing that the positive effects of fingolimod are apparent quite soon –within months – after initiation of treatment.

[transition music]

And now to our interview. I spoke with Professor Helen Tremlett, Canada research chair in neuroepidemiology and multiple sclerosis at the University of British Columbia when we were at the ECTRIMS conference in Barcelona in October. She has been studying sun exposure over the course of the lifetime and its relation to MS risk. While MS may affect an individual's likelihood to go out in the sun, studies may also need to consider the influence of sun exposure before the disease develops.

Interviewer – Dan Keller

What are you doing in this area?

Interviewee – Helen Tremlett

So I was presenting at ECTRIMS yesterday on a really interesting study based out of the Nurses' Health Study, and this was a collaboration from my group in Vancouver and Harvard School of Public Health; and that's Alberto Ascherio's group and Sandy Munger. So we were looking at sun exposure over the life course and associations with multiple sclerosis. So here we were looking at both aspects of the spectrum, if you can imagine; we were looking at sun exposure and future risk of multiple sclerosis, but also once an individual has developed multiple sclerosis, we were looking at the impact that potentially has on an individual in terms of their propensity to go outdoors in the daylight hours, outdoors in the sun.

MSDF

Right. So it may be the cart is before the horse in that sense; not that sun exposure is causing it, but their disability is causing less sun exposure?

Dr. Tremlett

We were looking at both sides of the equation. And I think it is important, particularly in a disease such as MS where onset of MS is a little bit fuzzy, I think, to look at sun exposure of the life course is important, and certainly our findings are indicating that. Because you want to know sunlight exposure in MS risk, but you also want to know, once someone's developed multiple sclerosis, how that influences their behavior outdoors and what implications that has if you're then trying to design the study to look at what causes MS.

You need to be really careful who you recruit, because if that person has already changed their behavior, then that may influence your findings, and you're not then actually looking at what causes MS at all, you're just looking at a consequence of the disease. So I guess that's the first part of why we wanted to do that.

And the second part is if having MS, if having a chronic condition, does influence your propensity or ability or desire to go outside, what consequence could that have for your health in terms of maybe your serum vitamin D levels or your melatonin levels, and that may have a consequence in terms of long-term health.

MSDF

You segmented people by where they were and at what ages.

Dr. Tremlett

It was pretty interesting. So, first of all, over ages 5 to 15, we found there that there was a 48% lower risk of MS for women living in high, relative to low, ambient UVB areas during their sort of childhood and early adolescent years. So that was pretty interesting. But we found, kind of to our surprise because it goes against other studies that are out there, we found that time spent outdoors in summer or winter wasn't significantly associated with MS risk in that age group, 5 to 15 years. But what we didn't realize is that it wasn't until we combined that outdoor behavior with the UVB, then we could see that there was an association. So we found that less time spent outdoors in summer in low ambient UVB areas—that was associated with a two-fold increased risk of multiple sclerosis.

That was an important step for us; I mean, it might, you know, sound obvious to combine those two, but it was an important step because other studies in smaller geographical areas such as Tasmania, or there's a study out of Norway in a small region of Norway, they can find an association between time spent outdoors in summer/winter and MS risk. But I think we couldn't find it in the US, because the US is at such a diversity of latitudes – the study spanned over 14 US states – so it wasn't until we looked at that outdoor behavior in context of ambient UVB that we could find the association.

And then, I suppose, our next step was to look at outdoor behavior over the life course. And this was really interesting, that we found some avoidance behavior was apparent in later life in multiple sclerosis. And maybe that comes as no surprise to people, but I think our numbers are interesting to put a concrete figure on it. So, for instance, by age 50, our MS cases were 60% less likely to report high relative to low outdoor exposure compared to controls, and that was in winter and in summer.

So the bottom line is people with MS, once they have MS, are not going outside as much, so they're not getting that UVB exposure, so potentially they're not making that vitamin D and serum vitamin D. And then the winter exposure's important as well, because potentially they're not getting the same melatonin production and inhibition, and that may have a really important role in terms of immunology, the circadian rhythm and your sleep cycle, which, again, all knocks back into overall health and immunology of MS. And there have been some presentations actually at this conference looking into melatonin and its association with relapses in MS, and that's pretty interesting.

MSDF

There's even some emerging thought that sleep is essential for good brain function in terms of taking out the garbage – glymphatics and things like that. So melatonin disturbances may actually have some further consequences in an inflammatory brain disease.

Dr. Tremlett

And there's some interesting studies, not that we did but others have done, looking at shift work and risk of MS. And shift work may be associated with increased risk of MS. Maybe melatonin ties into that as well.

MSDF

Is there also potentially an effect, besides on vitamin D and melatonin, that sun exposure itself has an effect on the immune system, maybe suppressing it?

Dr. Tremlett

Yeah, modulating it in some way. No, absolutely. We don't really know the mechanism. I mean, the obvious one would be sun on human skin at the right time of year on the right skin color can result in really high levels of serum vitamin D being produced. Sunlight exposure the minute it actually hits the skin surface can have a direct immunomodulatory effect. And then, obvious, sun hitting the eye. Melatonin is one of the pathways in there that may then impact the immune system.

MSDF

Is it possible to make any conclusions or even recommendations at this point?

Dr. Tremlett

No. It's an observational study, and we do actually need to do more analysis on this group of individuals. The main recommendations we could make from this study is informing how to design future studies, and also two things you could take from this in terms of recommendations.

First of all, we saw sun avoidance behavior in individuals once they've developed multiple sclerosis. That's really important because it really means that if you want to look at what is causing MS, do not take serum vitamin D levels or look at skin cancer risk, for instance, in individuals who already have MS, because they've already changed in compare to controls, adding further somehow differences are related to what causes MS, because these individuals have already changed their behavior because they've got a chronic disease. So that's the first statement, which might be a no-brainer for some people, but it's amazing how many studies are still published like that in the MS literature at the moment.

And I suppose the second piece is trying to understand if we are going to do an interventional study, what time period in an individual's life or within a population do you need to target in order to change the course and prevent the disease from occurring? And we're trying to understand that more, looking beyond the window age 5 to 15, look more into adulthood to see if ambient UVB is associated with MS risk later in life and into adulthood. And others have shown that there does seem to be an association even into adulthood, which is exciting because if you do want to do an intervention study, then you haven't necessarily missed the boat because you've not intervened during childhood. But, I mean, the real question is how do you intervene and what with? And that's another topic in itself.

MSDF

We'll leave that for another day. Thank you.

Dr. Tremlett

Thank you very much.

[transition music]

Next week, we'll continue our discussion with Professor Tremlett when she'll talk about her preliminary studies on pediatric MS patients and their gut microbiomes.

Until then, thank you for listening to Episode Sixty-Three of Multiple Sclerosis Discovery. This Podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Carol Cruzan Morton. Heather McDonald curated the MSDF drug database updates. Msdiscovery.org is part of the nonprofit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is Vice President of Scientific Operations.

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

For Multiple Sclerosis Discovery, I'm Dan Keller.

[outro music]

[intro music]

Host – Dan Keller

Hello, and welcome to Episode Sixty-Three of Multiple Sclerosis Discovery, the Podcast of the MS Discovery Forum. I’m Dan Keller.

We’ve just passed the winter solstice. What better time than the shortest daylight hours of the year to check in with research at the University of British Columbia on sunlight and MS? Today we talk with Dr. Helen Tremlett who is exploring sun exposure over a person’s life course and how that syncs with their MS risk and disease course.

In the weekly papers section on the MS Discovery Forum, this week’s list includes nearly 150 newly published research reports that could lead to better understanding and treatment of MS and related disorders.

We selected four papers as editor’s picks. In one paper, researchers think they may have the first experimental evidence that MS may start with damage or loss of myelin-making cells in the brain and spinal cord. In this new mouse model of progressive MS, experimentally damaged brain cells make it hard for the mice to walk. The mice recover when their brain cells repair on their own. Six months later, the MS-like disease returns. In the study, the team showed that nanoparticles targeting the autoimmune reaction prevent the second phase of the disease. The study shows support for an “inside-out” model of MS. That’s different from the “outside-in” model, in which some aspect about the immune system goes wrong and then initiates the attack on myelin-making cells. The paper is published in Nature Neuroscience by collaborating researchers from Northwestern University and the University of Chicago.

To grow and be healthy, all human cells need a signaling molecule named mTOR, named for the mammalian target of rapamycin. That’s true for myelin-making cells, or oligodendrocytes, as listeners may remember from an earlier podcast interview with Dr. Wendy Macklin. The ability to make myelin seems to depend on a key part known as mTOR complex 1, also called its raptor subunit. In a very basic advance, scientists have determined the atomic architecture of the raptor, or mTORC1, piece. The details are reported in the journal Science and provide a structural basis for studying mTORC1 function.

In another editor’s pick, a review of cases of pediatric neuromyelitis optica, or NMO, showed that new international diagnostic guidelines applied well to children. Unfortunately, they also found that children with NMO have delayed treatment and worse short-term outcomes compared to those with MS. The authors urged immediate adoption of the guidelines to select the best treatment and improve outcomes.

In the fourth editor’s pick, researchers found a potential new target to protect axons in a mouse model of neurodegeneration in multiple sclerosis. The target is a pore in the mitochondria, the cellular battery that provides energy. They designed a molecule to block the pore and showed it helped protect neurons and improved the mice’s mobility, all with minimal immunosuppression. The paper by mostly UK researchers is published in the Journal of Biological Chemistry.

Now, let’s take a look at the latest Drug Development Pipeline updates. The drugs with important additions and changes are dimethyl fumarate, fingolimod, glatiramer acetate, natalizumab, and rituximab. One update reflects findings from post-hoc analysis of clinical trial data showing that the positive effects of fingolimod are apparent quite soon –within months – after initiation of treatment.

[transition music]

And now to our interview. I spoke with Professor Helen Tremlett, Canada research chair in neuroepidemiology and multiple sclerosis at the University of British Columbia when we were at the ECTRIMS conference in Barcelona in October. She has been studying sun exposure over the course of the lifetime and its relation to MS risk. While MS may affect an individual's likelihood to go out in the sun, studies may also need to consider the influence of sun exposure before the disease develops.

Interviewer – Dan Keller

What are you doing in this area?

Interviewee – Helen Tremlett

So I was presenting at ECTRIMS yesterday on a really interesting study based out of the Nurses' Health Study, and this was a collaboration from my group in Vancouver and Harvard School of Public Health; and that's Alberto Ascherio's group and Sandy Munger. So we were looking at sun exposure over the life course and associations with multiple sclerosis. So here we were looking at both aspects of the spectrum, if you can imagine; we were looking at sun exposure and future risk of multiple sclerosis, but also once an individual has developed multiple sclerosis, we were looking at the impact that potentially has on an individual in terms of their propensity to go outdoors in the daylight hours, outdoors in the sun.

MSDF

Right. So it may be the cart is before the horse in that sense; not that sun exposure is causing it, but their disability is causing less sun exposure?

Dr. Tremlett

We were looking at both sides of the equation. And I think it is important, particularly in a disease such as MS where onset of MS is a little bit fuzzy, I think, to look at sun exposure of the life course is important, and certainly our findings are indicating that. Because you want to know sunlight exposure in MS risk, but you also want to know, once someone's developed multiple sclerosis, how that influences their behavior outdoors and what implications that has if you're then trying to design the study to look at what causes MS.

You need to be really careful who you recruit, because if that person has already changed their behavior, then that may influence your findings, and you're not then actually looking at what causes MS at all, you're just looking at a consequence of the disease. So I guess that's the first part of why we wanted to do that.

And the second part is if having MS, if having a chronic condition, does influence your propensity or ability or desire to go outside, what consequence could that have for your health in terms of maybe your serum vitamin D levels or your melatonin levels, and that may have a consequence in terms of long-term health.

MSDF

You segmented people by where they were and at what ages.

Dr. Tremlett

It was pretty interesting. So, first of all, over ages 5 to 15, we found there that there was a 48% lower risk of MS for women living in high, relative to low, ambient UVB areas during their sort of childhood and early adolescent years. So that was pretty interesting. But we found, kind of to our surprise because it goes against other studies that are out there, we found that time spent outdoors in summer or winter wasn't significantly associated with MS risk in that age group, 5 to 15 years. But what we didn't realize is that it wasn't until we combined that outdoor behavior with the UVB, then we could see that there was an association. So we found that less time spent outdoors in summer in low ambient UVB areas—that was associated with a two-fold increased risk of multiple sclerosis.

That was an important step for us; I mean, it might, you know, sound obvious to combine those two, but it was an important step because other studies in smaller geographical areas such as Tasmania, or there's a study out of Norway in a small region of Norway, they can find an association between time spent outdoors in summer/winter and MS risk. But I think we couldn't find it in the US, because the US is at such a diversity of latitudes – the study spanned over 14 US states – so it wasn't until we looked at that outdoor behavior in context of ambient UVB that we could find the association.

And then, I suppose, our next step was to look at outdoor behavior over the life course. And this was really interesting, that we found some avoidance behavior was apparent in later life in multiple sclerosis. And maybe that comes as no surprise to people, but I think our numbers are interesting to put a concrete figure on it. So, for instance, by age 50, our MS cases were 60% less likely to report high relative to low outdoor exposure compared to controls, and that was in winter and in summer.

So the bottom line is people with MS, once they have MS, are not going outside as much, so they're not getting that UVB exposure, so potentially they're not making that vitamin D and serum vitamin D. And then the winter exposure's important as well, because potentially they're not getting the same melatonin production and inhibition, and that may have a really important role in terms of immunology, the circadian rhythm and your sleep cycle, which, again, all knocks back into overall health and immunology of MS. And there have been some presentations actually at this conference looking into melatonin and its association with relapses in MS, and that's pretty interesting.

MSDF

There's even some emerging thought that sleep is essential for good brain function in terms of taking out the garbage – glymphatics and things like that. So melatonin disturbances may actually have some further consequences in an inflammatory brain disease.

Dr. Tremlett

And there's some interesting studies, not that we did but others have done, looking at shift work and risk of MS. And shift work may be associated with increased risk of MS. Maybe melatonin ties into that as well.

MSDF

Is there also potentially an effect, besides on vitamin D and melatonin, that sun exposure itself has an effect on the immune system, maybe suppressing it?

Dr. Tremlett

Yeah, modulating it in some way. No, absolutely. We don't really know the mechanism. I mean, the obvious one would be sun on human skin at the right time of year on the right skin color can result in really high levels of serum vitamin D being produced. Sunlight exposure the minute it actually hits the skin surface can have a direct immunomodulatory effect. And then, obvious, sun hitting the eye. Melatonin is one of the pathways in there that may then impact the immune system.

MSDF

Is it possible to make any conclusions or even recommendations at this point?

Dr. Tremlett

No. It's an observational study, and we do actually need to do more analysis on this group of individuals. The main recommendations we could make from this study is informing how to design future studies, and also two things you could take from this in terms of recommendations.

First of all, we saw sun avoidance behavior in individuals once they've developed multiple sclerosis. That's really important because it really means that if you want to look at what is causing MS, do not take serum vitamin D levels or look at skin cancer risk, for instance, in individuals who already have MS, because they've already changed in compare to controls, adding further somehow differences are related to what causes MS, because these individuals have already changed their behavior because they've got a chronic disease. So that's the first statement, which might be a no-brainer for some people, but it's amazing how many studies are still published like that in the MS literature at the moment.

And I suppose the second piece is trying to understand if we are going to do an interventional study, what time period in an individual's life or within a population do you need to target in order to change the course and prevent the disease from occurring? And we're trying to understand that more, looking beyond the window age 5 to 15, look more into adulthood to see if ambient UVB is associated with MS risk later in life and into adulthood. And others have shown that there does seem to be an association even into adulthood, which is exciting because if you do want to do an intervention study, then you haven't necessarily missed the boat because you've not intervened during childhood. But, I mean, the real question is how do you intervene and what with? And that's another topic in itself.

MSDF

We'll leave that for another day. Thank you.

Dr. Tremlett

Thank you very much.

[transition music]

Next week, we'll continue our discussion with Professor Tremlett when she'll talk about her preliminary studies on pediatric MS patients and their gut microbiomes.

Until then, thank you for listening to Episode Sixty-Three of Multiple Sclerosis Discovery. This Podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Carol Cruzan Morton. Heather McDonald curated the MSDF drug database updates. Msdiscovery.org is part of the nonprofit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is Vice President of Scientific Operations.

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

For Multiple Sclerosis Discovery, I'm Dan Keller.

[outro music]

Transcript will be available Thursday, 24 Dec

[intro music]

Host – Dan Keller

Hello, and welcome to Episode Sixty-One of Multiple Sclerosis Discovery, the Podcast of the MS Discovery Forum. I’m Dan Keller.

In this podcast, Dr. Yanming Wang of Case Western Reserve University in Cleveland, Ohio, discusses a solution to the vexing problem of how to track changes in myelin in the brain and spinal cord, a measurement believed to be especially important for new candidate drugs to restore this insulating sheathing around axons.

First, here are some new items in the MS Discovery Forum.

A new data visualization showcases the collaborations among authors who published papers reporting the results of clinical trials in progressive forms of multiple sclerosis in the last 30 years. You can find the network map on msdiscovery.org under “Research Resources.” You can mouse over circles in the graphic to find researchers' names. Click and drag the circles to animate the map and reveal connections.

In research news, a Swedish team took the first steps toward finding potential disease markers in the immune cells of asymptomatic people with MS and with seasonal allergies. The study pinpointed three key proteins that may transform normally protective T cells into ones that attack myelin in the case of MS. The three proteins are transcription factors, which glom on to DNA and control which genes turn on and off. According to data from genome studies, the proteins are more common in genetic regions associated with disease, strengthening the case for their role in MS. Finally, the three proteins act differently in people with immune-related diseases, including multiple sclerosis, according to tests on blood samples. Ultimately, the researchers want to learn if they can detect multiple sclerosis and other autoimmune conditions much earlier.

[transition music]

And now to our interview. MSDF caught up with Dr. Yanming Wang last month at the 2015 World Congress of Neurology meeting in Santiago, Chile. We discussed his solution to what has been a missing link in MS research and practice; that is, how to image myelin -- not just lesions on an MRI, but how to tag the substance itself using a biomarker for molecular imaging called M-E-D-A-S, or "mee-das." Going beyond diagnosis, Dr. Wang told us it may eventually allow clinicians to get a better handle on disease progression and efficacy of treatments.

Interviewer – Dan Keller

You had referred to molecular imaging of myelin as the missing link. Why is this the missing link?

Interviewee – Yanming Wang

Because molecular imaging has really transformed how we practice medicine today, and it has become a standard care for virtually many neurological diseases. However, in multiple sclerosis, there's still no effective imaging technique in place that can help physicians to monitor not just for diagnosis, but also to monitor the disease progression.

MSDF

And would this be useful also in monitoring potential therapies?

Dr. Wang

Exactly. There's a lack of imaging technique that allow people to monitor the drug efficacy, particularly for those drugs that try to repair the myelin damage in the CNS.

MSDF

How would this differ from MRI imaging, what you see there, versus having a radioactive biomarker?

Dr. Wang

Currently, MRI is the commonly used imaging modality in MS, however MRI provides only anatomical information and also detect brain lesions. However, those lesions detected on MRI are not specific for myelin pathology.

MSDF

You do have a compound now, [11C]MeDAS, which would be specific for myelin. Is that right, is it very specific for myelin?

Dr. Wang

Exactly. It's very specific for myelin, because the advantage it has over MRI is that that is truly a molecular imaging modality which uses myelin-specific radiotracers that allow to quantitatively monitor the myelin damage and myelin distribution in the brain. So for this reason, we developed a specific radiotracer that can selectively bind to myelin with high affinity, so that we could directly image the myelin distribution.

MSDF

How quickly does it reach the CNS and you can image?

Dr. Wang

It takes minutes, literally, for the radiotracer to penetrate the BBB and enter the brain, and then the whole process takes only 60 minutes.

MSDF

Can you briefly describe your rat model where you're using lysolecithin as an MS model, and then what you did with your marker?

Dr. Wang

Lysolecithin model is an established model of focal demyelination in the brain, so we used that model to test our compounds to monitor the demyelination and remyelination. So after injection of MeDAS, the compounds could readily enter the brain and selectively bind to the myelin. And then at the peak of the disease, which is a peak of the demyelination, the brain uptake of the compounds is lowest, versus when the brain is recovered, then the brain uptake of the compounds is increased. So this demonstrated the in vivo specificity of the radiotracer for myelin.

MSDF

And you can image myelin on the way down and on the way up; you have this hepatocyte growth factor which causes some remyelination?

Dr. Wang

Right, exactly. In collaboration with my colleague, Bob Miller. So we'd use this imaging modality to see if we can monitor the drug efficacy for remyelination. So we'd give this HGF, which is a growth factor that promotes remyelination, and then we could use this imaging technique just to monitor the increase of remyelination after the drug treatment.

MSDF

Everything right now is in animals. Do you have plans for any human trials?

Dr. Wang

Yes, we are working on this paperwork required by FDA to put these compounds in humans.

MSDF

Is the compound so far nontoxic; it's diamino stilbene, is that right? Does it have any estrogenic effects or other toxic effects?

Dr. Wang

No. We have done systematic toxicity studies and there's any adverse effects in animal models so far.

MSDF

What do you see as the clinical utility of this if it enters the human realm?

Dr. Wang

It's going to be a very powerful tool for diagnosis and prognosis, and also particularly for evaluation of drug efficacy. As you know, currently pharmaceutical companies and academic investigators are all trying to develop new drugs that can repair myelin damage in order to restore the biological functions. However, there's a lack of imaging tools in place that allow them to monitor such myelin repair therapies, and this could provide the missing link for this endeavor.

MSDF

Does PET imaging with this compound correlate at all with what's seen on MRI, especially in a kinetic sense following time course?

Dr. Wang

Well, yes. In the wonderful publication in Annual Neurology a couple years ago, we did demonstrate that this PET imaging technique can be used as an imaging marker that correlates with the disease progression in terms of the severity of the symptoms in animal models, in the EAE models. The EAE rat, for example, its appearance, the relapsing or remitting stage, and that we could use this imaging marker to correlate nicely with the symptoms. And this is one of important application if we put this into clinical use.

MSDF

Is this compound the end-all and be-all, or are you developing others, or have some gone by the wayside for various reasons?

Dr. Wang

This compound, and also this imaging technique, could be used not just only in MS, but can also be used in many other neurological diseases, such as Alzheimer's disease, spinal cord injury, and stroke, for example, because all of these neurological diseases are associated to some degree with the myelin damage.

MSDF

Have we missed anything important, anything to add?

Dr. Wang

Again, I think the imaging technique, particularly molecular imaging technique based on positron emission tomography, is lagged behind in the field of neurological diseases because of the complexities of the brain and the lack of molecular probes that could advance our understanding, also facilitate the drug discovery.

MSDF

I appreciate it. Thank you.

Dr. Wang

Oh, thank you very much then.

[transition music]

MSDF

Thank you for listening to Episode Sixty-One of Multiple Sclerosis Discovery. This Podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Carol Cruzan Morton. Heather McDonald curated the MSDF drug database updates. Msdiscovery.org is part of the nonprofit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is Vice President of Scientific Operations.

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

For Multiple Sclerosis Discovery, I'm Dan Keller.

[outro music]

Transcript will be available Tuesday, 17 November 2015

[intro music]

 Host – Dan Keller

Hello, and welcome to Episode Fifty-Nine of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.

In our previous podcast, you heard about a group of leading MS researchers and clinicians calling for a big change in improving care for people with MS. The new report, called Brain Health – Time Matters in MS, makes the case for a therapeutic strategy to minimize disease activity. The report advises early diagnosis and treatment, and regular monitoring of disease activity. The report urges patients, physicians, health care payers, and policy makers to support the goal of life-long brain health.

In this podcast, another one of the report authors, Dr. Helmut Butzkueven, talks about what the new treatment target means for patients and their doctors in the real world.

This is one of our extra podcasts from the big MS meeting in Barcelona talking about ways that evidence from research can be translated now into better MS outcomes

But first, here are some new items in the MS Discovery Forum.

Every week, MSDF lists the latest scientific papers on MS and related disorders, with links to the abstracts on PubMed. Of more than 110 new studies published last week, we selected three as editor’s picks.

MS has been traditionally viewed as a T cell–driven disease, but a new paper from Canadian researchers introduces another villain—a rogue type of B cell in people with MS that may fuel inflammation in two ways. This may be why general B cell depletion seems to work so well in MS and may lead to more targeted treatments.

In a new twist on dietary fat and autoimmune disease, German researchers report that certain fats work through gut microbes to exert both good and bad effects. In mice, they found certain fats were protective against inflammatory fats. They have moved on to testing in healthy humans and hope to study the impact in people with MS.

A cost-effectiveness study from Spain says do not judge a drug by its price alone. Glatiramer acetate may be more expensive than interferon-beta, but fewer relapses and reduced spasticity may make it more cost effective. Interesting, but you can be sure this fuller economic look will not be the last word on drug costs.

[transition music]

And now to our interview with Dr. Helmut Butzkueven, who directs the MS services at the Royal Melbourne Hospital and the Box Hill Hospital in Melbourne, Australia. We spoke with him at the recent European Committee for Treatment and Research in MS, or ECTRIMS, meeting in Barcelona about the Brain Health report that was launched at the meeting. The main thrust of the report – aimed at the broad MS community – is that time matters in MS. The report lays out several goals to maximize brain health over the lifetime. A critical one is early intervention.

Interviewee – Helmut Butzkueven

We know that early disease activity sets up long-term problems. However, early disease activity is often relatively silent to the eye. It’s not silent to the eye of the MRI machine and other monitoring tools that we have. So we would like clinicians and patients, not actually just in early disease, but starting right from the start to have a proactive monitoring approach to jointly assess their disease activity and take action if things are not going well.

Interviewer – Dan Keller

How much of an emergency is it? If someone finds out they have a cancer diagnosis, they rush to a surgeon, oftentimes. If they find out they have high cholesterol, they might take a year or two to decide to get on a statin. So what’s the time frame we’re talking about here?

Dr. Butzkueven

I think the appropriate time frame to think about is months, actually. We think that an MRI scan should be performed approximately every 12 months to assess disease activity, to assess how your current treatment is performing. So it’s not seconds or minutes; thankfully, multiple sclerosis isn’t exactly like an acute stroke or a heart attack. But it’s also not a time, particularly early in the disease when you could be setting up these kind of strategies, to just leave people be. We need to, when we first see patients, articulate our monitoring goals.

MSDF

And how quickly should someone, when they’re referred and there’s a putative diagnosis, get that scan initially?

Dr. Butzkueven

As soon as possible. I mean, scans are crucial, obviously, for diagnosis – accurate diagnosis, as well as for setting up the monitoring phase, because the first scan can then be compared to the next scan, and so on.

MSDF

What other goals are there for treatment and management?

Dr. Butzkueven

The key things that we want to really focus on, apart from what we’ve already discussed which is early diagnosis and articulating a treatment and monitoring plan to maximize brain health, is a joint approach. So for people with MS and doctors to both be empowered to jointly manage the disease. So this includes, of course, increasing consultation time, giving people time to discuss their MS with their managing team. I think this kind of move away from paternalistic medicine, to empowering patients to be part of the management process to self-manage is hugely important. That’s just in step with the modern world.

The other thing is more indirect. Across the world, we face huge differences in access to disease-modifying drugs. Some of us living in the United States and Australia in Germany, Switzerland are luckier than others. And we really need to provide evidence to government that disease-modifying drugs are worth funding.

MSDF

Or else what happens?

Dr. Butzkueven

Else people, and ultimately governments, incur the costs of markedly worse disability.

MSDF

To empower patients takes certain knowledge and, I suppose, permissions or rapport with the physician. And to empower the physician, I suppose, takes knowledge, evidence, consult. So are these two different things? Do they move in parallel, but they require different activity?

Dr. Butzkueven

Yes, they do. Of course they do. To some extent, changing practice in an interaction can come from either side of the interacting party, but certainly patients, on the whole, probably need to be more demanding. They need to have access to evidence, and I’m going to say something controversial, to actually help assess the clinical care that they are receiving. So people should say, for example, if this report, the evidence suggests that perhaps we should be doing something else. What do you think?

Physicians, as I said, need to be strongly encouraged to have a priori a specific plan. If you were someone with MS, and we saw you for the first time in our clinic, we should be telling you what the goals are. We should be telling you what our scheme of monitoring is going to be to maximize your outcome, to maximize your brain health.

MSDF

What kind of a role can longitudinal databases play in changing policy?

Dr. Butzkueven

They’re really the only source of long-term data. MS is a disease which you’re going to have for decades, once you’re diagnosed with it, and it likely will cause you and your government very significant costs over that time. But those costs can only be measured if we measure those outcomes, and the only way to really measure them is longitudinally. So databases embedded in the real-world healthcare collecting just a minimum of information on as many MS patients as possible can be enormously powerful, doing the sums in the first place, actually understanding how much disability there is; how much can be prevented with appropriate treatment strategies; and, dare I say it, how much money government could save.

MSDF

MRIs are now a powerful tool. Other medical specialties have had all sorts of invasive measures in the past. You could take biopsies of skin, breast, prostate, liver. You never had an assessment tool this powerful, but now this one is fairly noninvasive. It’s completely noninvasive. What can it tell you? I mean, people look for lesions, but there’s much more to be derived.

Dr. Butzkueven

Yes, of course. Lesions is still a key outcome, but the other thing is brain shrinkage – brain atrophy. So we, increasingly, understand that people who are experiencing significant brain loss – brain tissue loss – early in their MS will do worse, in the long-term. So here we have another target for monitoring. And people might say, well, I do an MRI scan, but there are no lesion changes reported. There’s no volume changes reported. But this world is changing rapidly. Image recognition analysis tools are advancing very quickly. I predict, within two or three years, routine MRI will actually spit out these metrics for us. At the moment, a lot of reporting, unfortunately, in the world is still what we would call qualitative rather than quantitative. But we’re going to start seeing those numbers, and we need to be ready to act on them.

MSDF

How much faster does the brain, in an MS patient without treatment, atrophy or lose volume compared to an age-matched control?

Dr. Butzkueven

So this is a question that I can answer in two ways, I think, to illustrate the concept. I could say it’s five to seven times faster. What I’m talking about there is averages, medians if you like. What I should be saying is that it could be anything. Your trajectory, as an MS patient, could be exactly within the normal range, I mean, sadly – particularly over the age of 30 – all of us lose a bit of brain volume a year: 0.3%, 0.4%. In MS, that could be your trajectory, and that would be fantastic. On the other hand, you could the person losing 3%, 4% – 10 times, 15 times normal. And we could pick that within a year or two, and that is the time to intervene, not when that ultimately results five, six, ten years later in progressive disease.

MSDF

You’ve made the analogy of managing MS to a new car and its warranty. Can you tell me about that?

Dr. Butzkueven

I was really just trying to say that plans for keeping things well, keeping things in shape, are quite prominent in society. So this analogy is simple. You buy a new car. What you get with it is a service book. The service book gives you a plan for managing your car. At 6 months, there’ll be a little tire change, oil change; 12 months there’ll be a major service, and so on. And the thing is, as a customer, I mean, you buy the car. It’s already there. It’s the same thing. We want clinicians and patients to demand and to deliver a plan. This is how we’re going monitor your MS to maximize the health of your brain.

MSDF

So this is your 6 month service. This is your 12 month service.

Dr. Butzkueven

Exactly. So, for example, in might be we will see you every 6 months, and we’ll do a neurological examination. We might do a particular cognitive test. We will do a repeat MRI scan, ideally on the same machine, once a year. We will be looking for the following: we will take action if things are going badly. If things are going well, then we’re reassured. But we need people with MS to demand this, and we need clinicians to deliver these plans.

MSDF

I don’t mean to make light of the situation of having the disease, but I think people respond well to something they already know, like a service plan.

Dr. Butzkueven

Yes, sure. I guess that’s why I’m using that analogy. Maybe we should say we need a service plan for MS.

MSDF

Is there anything we’ve missed or important to add?

Dr. Butzkueven

Nothing. We’ve covered the key recommendations of the report: access to early diagnosis, consideration of early treatment, a service plan, empowerment of people with MS to actually have accurate information, and being empowered in shared decision-making, and finally, the health economics situation, powered by clinicians – more and more clinicians – collecting long-term outcomes data on people with MS.

MSDF

And the Brain Health report is freely available, and we will link to it. I appreciate it. Thank you.

Dr. Butzkueven

It’s a pleasure. Thank you for talking with me.

[transition music]

MSDF

Thank you for listening to Episode Fifty-Nine of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Carol Cruzan Morton. Heather McDonald curated the MSDF drug database updates. Msdiscovery.org is part of the nonprofit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is Vice President of Scientific Operations.

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

For Multiple Sclerosis Discovery, I'm Dan Keller.

[outro music]

[intro music]

Host – Dan Keller

Hello, and welcome to Episode 58 of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.

A group of people are calling for a big change in improving care for people with MS. There may be no cure for MS yet, but there are a lot of ways to improve their outcomes. In this podcast, one of the ringleaders, Dr. Gavin Giovannoni, talks about a new push to use long-term brain health as a goal in MS treatment.

The new report, called Brain Health, makes the point that time matters in MS. The authors draw on more than 300 research studies to show evidence that brain tissue can be preserved with early and effective treatment, and regular monitoring of disease activity. The report urges patients, physicians, health care payers, and policy makers to support the goal of life-long brain health.

This podcast gives you the main take-home points from the Brain Health initiative, launched at the recent MS meeting in Barcelona, Spain. We will have extra podcasts for you in the coming weeks about other ways that evidence from research can be translated now into better MS outcomes.

But first, here are some new items in the MS Discovery Forum.

In the discussion section, a team of graduate students wants to hear from people with MS and their families. The team is from Santa Clara University, located in the heart of Silicon Valley in California. They have a class project to design a software product to assist people impacted by MS. Help them out by completing their survey.

Coming up on our meetings and events list is next week’s World Congress of Neurology in Santiago, Chile. MSDF will be there gathering new podcast interviews. If you, too, will be at the conference and would like to meet with us – or if you’re interested in being interviewed about your research for a future podcast – please email us at editor@msdiscovery.org.

The meeting list includes many specialty conferences and seminars of all the different kinds of scientific expertise that goes into understanding MS, from immunology to myelin biology, genetics, and brain and spinal cord imaging. Please add your meetings, workshops, and seminars. This is just one of the ways that MSDF shares information across the many different specialty areas to advance treatments for MS. Help us by adding other MS-research-related events. It’s free to post.

Our Drug-Development Pipeline contains 44 investigational and approved agents for MS. Last week, we added results from one new trial, we updated subject matter from four other trials, and we added eight other pieces of information to the database. One update summarizes findings gathered from a 15-year follow-up visit for participants in the PRISMS interferon beta-1a trial.

[transition music]

And now to our interview with Dr. Gavin Giovannoni, head of neurology at Barts and The London School of Medicine and Dentistry in the U.K. We spoke with him at the recent European Committee for Treatment and Research in MS, or ECTRIMS, meeting in Barcelona about the Brain Health report that was launched at the meeting. The main thrust of the report – aimed at a broad audience of MS community members – is that time matters in MS.

Interviewer – Dan Keller

In terms of the Brain Health report, can you give me a broad overview of what the intent was and what you hope to accomplish?

Interviewee – Gavin Giovannoni

I mean, the real issue is to try to raise awareness and use it as a platform for trying to get policy changed. And the target audience is just the MS community, as well as health care providers, payers, politicians, etc. And one of the things we’re beginning to realize now as we have more effective therapies, and we begin to learn more about MS, is that we are compromising the health of our patients by not treating them quickly enough or manage them quickly enough. I mean, there are large delays in patients being diagnosed, getting access to treatment, and when they’re on treatment, they’re not being monitored actively.

And there’s now emerging data that if you’re on a therapy, and you’ve got ongoing disease activity, you don’t do very well in the long-term. So the idea is to try and encourage people to treat to a target, monitor, and escalate rapidly. So it’s really trying not to waste time, too, essentially. And we borrow the term, “Time is Brain” from “Time Matters” from the stroke, where we know that, you know, every minute counts. And we would like to get the attitude across to people who are treating MS that every week, every month counts.

MSDF

At the initial diagnosis, how quickly should things move along, scanning, treatment?

Dr. Giovannoni

I mean, we’ve got guidelines within our socialist healthcare system, the NHS, to get the diagnostic phase over with in a four-week period. If you’ve got the disease, it’s very anxiety-inducing, the whole process. In reality, you’d like to get it over with in days. And then you need to start the counseling and education process. And I think you can’t rush people onto therapy within days because the holistic approach is people got to understand their disease, the implications of the illness, the prognosis. They’ve got to come to terms with it as well before you can actually start discussing the implications of therapy, which may be life-long. So I’m not talking about this is like stroke – you have that thirteen minutes – I think you need to try and shorten the whole process and be active about it, not be passive.

Most clinicians in the world now just monitor their patients clinically. They don’t monitor them with MRI scans. They just wait for them to break through. Sometimes they accept minor relapses as just being part of the disease, and I think now that we’ve got more effective therapies, we shouldn’t be accepting any breakthrough activity. We should be escalating people to more effective therapies. And the data is becoming really strong that active disease, in the form of relapses or MRI activity, does portend a poor prognosis, so you want to switch it off.

MSDF

The report laid out some specific goals. Can you delineate some of those?

Dr. Giovannoni

The main goal is speeding up the whole process, so a rapid diagnosis, rapid initiation of treatment, monitoring, rapid escalation or possibly even flipping the pyramid – if they’ve got a bad prognostic profile, give the more effective therapies. Also, collect data so by monitoring, you hopefully will change behavior. And then the other thing that’s hidden is the cost effectiveness of these treatments. So, we need to make systems available to provide these drugs at cost effective prices, particularly in countries that are resource poor. It’s fine talking about North America and Europe – relatively wealthy areas of the world – where we have insurance systems to pay for these expensive new emerging therapies. But if you just to any of the developing countries, people with the disease don’t have access to disease-modifying treatments. We’re just letting the disease run its natural course, and I find that very upsetting.

There’s a whole literature and emerging dataset on brain health from, mainly, the dementia – Alzheimer's field – and some of it’s applicable to MS: getting patients to stop smoking; they must exercise regularly, try to avoid drugs that affect cognition, avoid excessive alcohol, sleep properly. Comorbidities must be managed actively. By that I mean hypertension, diabetes, etc. So there’s all that lifestyle, comorbidity issues that also need to be focused on. It’s basically making neurologists and healthcare professionals aware that there’s more to the brain in MS than just inflammation. We need to think of it holistically and take it seriously.

MSDF

What do you see as some of the barriers to implementing all these things that you’re recommending?

Dr. Giovannoni

The barriers I wish I could answer it easily. I mean, we know that there’s slow adoption of innovation. Certain fields are more slow at adopting innovation than others, and I think neurologists, intrinsically, are quite conservative. And up until we had therapies in MS, we were just diagnosticians and giving prognoses. Now that we’ve got treatments, we need to adapt to the fact that we’ve got therapies that can make a difference to people with MS. So the slow adoption is attitude, culture, and regulatory hurdles. There’s cost hurdles. Health insurance companies don’t pay for our monitoring, in large parts of the world, so you’re going to have to fight with them to be able to monitor with MRI scans. Patients themselves – try and nudge them to stop smoking and eat properly and exercise. It’s easier said than done. I mean, this is a global population issue, and you know, why should people with MS be any different to the general population. So it’s not easy. We need to think creatively about how we get this done.

MSDF

But it sounds like nihilism should be passé, if in the past, all you could do was diagnose and hope for the best. Now that’s really not the situation.

Dr. Giovannoni

Yes, but I think there’s another form of nihilism. And so in the past, we had therapeutic nihilism where we didn’t give any therapies. I think we’ve got a form of subliminal nihilism in the sense; we put people on less effective therapies. We’re not monitoring them, but their disease remains active. I call it smoldering MS. Unless we monitor with sensitive MRI techniques, possibly other monitoring, we’re not picking up the smoldering MS. And so I think we’re potentially leaving a whole generation of people with smoldering MS to obviously a better outcome than they would have had with no therapy, but not as good an outcome if they would be as connected to more effective therapies.

So that the subliminal nihilism, I just thought about that term, it kind of captures what I’m trying to, because, you know, what we see affects behavior. If we don’t see it, we don’t change our behavior. So part of this report is to make people observe, measure, monitor. And if they see activity, hopefully, it’ll change their behavior.

MSDF

In so many specialties, people say, well, I don’t treat lab values. I don’t treat images. I treat patients. But in this case, it seems like you do intervene when there is an imaging change.

Dr. Giovannoni

Yes, because we now have data, so this has got to be evidence-driven. And we’re not saying every recommendation in the policy report’s got unclad evidence about it. There is some weakness in the evidence base, but we think the evidence base is strong enough to make the recommendations. And we’ve actually put into the report that where there isn’t enough evidence, we need to generate more evidence. And to be honest with you, we need a population study comparing people managed with routine care versus patients treated to target with rapid escalation. MSBase has kind of done that without the MRI monitoring, because they don’t have MRI data in their database. They’re just looking at the clinical, letting people break through with relapses versus relapse-free, in those that are rendered activity-free clinically, do much, much better. And I think that tells us that if we were using MRI, it will even be better. So at least we know that MRI activity is a surrogate for relapses.

And there’s also scientific principle. We know, under the microscope, inflammatory lesions are not benign. They’re associated with transected axons, neuronal loss, etc. So it’s hard to deny the scientific principle of allowing lesions to continue to be active. To me it makes no biological sense. And this is not new. We’re just stealing the ideas from rheumatology and nephrology. They treat to target. They try and suppress inflammation as much as possible, and they’ve had incredible success. And they didn’t do it from an evidence base; they did it from a scientific principle.

And, as they collected their data in registries, they confirmed what the science showed. Long-term follow-up with these patients has shown that if you treat to target in rheumatoid arthritis and with rapid escalation, you protect joints. And joint replacements now in rheumatoid patients has plummeted by more than 80 percent.

I think our metric will have to be walking sticks and wheelchairs. We’ll see the use of walking sticks and wheelchairs plummet. Maybe employment – that’s the other thing we’re trying to highlight is most of the early disability in MS is not physical, it’s cognitive. And the early unemployment rates that occur before people become physically disabled are driven by cognitive problems which manifest as cognitive fatigue. So, you know, what we’re trying to do is also shift people’s attention away from just physical disability and think about cognition, which is an early disability. And hopefully, if we can treat people as early as possible, we’ll protect their cognition and allow them to continue working. So maybe the metric should be employment, as one of the metrics.

MSDF

So many reports in all areas come out and they’re sort of one-shot deals. Do you have a plan for giving this thing legs so that it’s not just buried once it came out?

Dr. Giovannoni

Yes, so we’ve got a whole lot of initiatives following on this. We’ve put together a grant application package. We’ve got a dissemination plan, both at a regional and international level. We’ll also want it connected to audit tools, so provide some audit tools where you can actually audit—measure—what we’re trying to achieve and, hopefully, use that as a quality metric. We think we if can start measuring, people will change their behavior. We also want to create an audit tool for people with MS to audit their own service. So in other words, they will go in and say, am I being monitored? How am I being monitored, just clinically or with MRI? And ask the right questions, and, hopefully, activating patients to ask their clinicians to be monitored may also change behavior.

We don’t want it to be a name and shame type thing. We want it to be a positive thing, by measuring, we’ll change behavior, so that’s what we want to do. The only thing, though, it can’t be done quickly. We need to get buy in from the whole community, so we’ll have to have an engagement program to get there. Get a competition going, international competition where people can provide creative ideas to try and help with viral dissemination. So get an infographic or a movie or a play or a book or a poem, something that can go viral. And then we’re going to, hopefully, have funding to update the report.

We are going to have a very active website where people can download the report. And we’re going to try and create content around Brain Health. Another thing we’re going to be doing is looking for funding to translate it into other languages. We’ve already had requests from several non-English speaking nations for translations. So the Dutch want it translated. South America wants it in Spanish. We’ve had a request from the Japanese, Russians. And so if we can get it translated, we’re probably not going to get the whole document translated. We’re going to make executive summaries, one for patient focused, one for clinicians, one for policy makers. And we’ll, hopefully, get those translated into multiple languages.

MSDF

MSDF will put the link on the site so that people can access it in English now. Is there anything to add or we’ve missed?

Dr. Giovannoni

I think we’ve got to start changing the behavior of neurologists in the sense that we need to make them think of their responsibility for looking after people with MS’s brains. We tend to focus on making them relapse free. If we actually shifted the target away from being relapse free but maintaining brain health, so these people can age as normally as possible – we’re not trying to say that people with MS will age normally, but we need our brains for when we get older. So if they start taking responsibility for the holistic management of MS, I think we’ll get the momentum going where people will be much more actively managing MS.

[transition music]

MSDF

Thank you for listening to Episode 58 of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Carol Cruzan Morton. Heather McDonald curated the MSDF drug database updates. Msdiscovery.org is part of the nonprofit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is Vice President of Scientific Operations.

MSdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

For Multiple Sclerosis Discovery, I'm Dan Keller.

[outro music]

[intro music]

Host – Dan Keller

Hello, and welcome to Episode Fifty-Seven of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.

This week’s podcast comes to you from last week’s big MS meeting in Barcelona, Spain, with an interview with Dr. Timothy Vollmer, who gives his take on the early results of a large Phase 3 study of ocrelizumab for primary progressive MS. The experimental drug blocks circulating B cells.

We will have several extra meeting-related podcasts for you in the next two weeks. In the next one, Dr. Gavin Giovannoni talks about a new push to use long term brain health as a goal in MS treatment. And Dr. Vollmer will return in the coming weeks to discuss the Denver treatment experience with another B cell blocking drug, rituximab. But first, here are some new items in the MS Discovery Forum.

Every week MSDF lists the latest scientific papers related to MS with links to the abstracts on PubMed. Of nearly 100 new studies published last week, we selected three as editor’s picks.

Two of our editor’s picks come from a larger collection on MS in JAMA Neurology. One study reports on an equivalence clinical trial comparing a generic glatiramer acetate, Synthon, with Copaxone, the branded glatiramer acetate, for relapsing remitting MS. A global team of investigators found equivalent efficacy, safety, and tolerability in the randomized, controlled trial. The findings provide reassurance about well-made generics for patients and neurologists, say other researchers in an editorial. But the whole idea of generics is to make a dent in the skyrocketing costs of MS drugs, and the generic is priced at $63,000 a year instead of $65,000 and $74,000 for the two versions of the branded drug.

Another paper in the same JAMA Neurology checked to see what the vitamin D levels of nearly 1500 people treated with interferon beta-1B might say about the course of their disease. Higher vitamin D levels were associated with fewer new active lesions in the mostly white, mostly female patients with relapsing remitting MS, but there was no correlation with clinical disability or brain atrophy.

Our third editor’s pick is a paper investigating the cancer risk from cladribine compared to other MS disease modifying treatments. A large Phase 3 study showed the experimental drug to be highly effective in relapsing remitting MS, with nearly half of patients showing no evidence of disease activity after two years and two courses of the treatment. But it was refused a license by the European Medicines Agency in 2013. Now, based on their new meta-analysis of eleven studies, the authors say they cannot confirm nor deny a cancer risk, and that cladribine should be investigated further as an MS therapy.

Our drug development pipeline contains 44 investigational and approved agents for MS. Last week, we added results from two new trials, we updated information from 16 other trials, and we added 20 other pieces of information. Trial updates include findings about ocrelizumab’s ability to reduce relapses and minocycline’s capacity to reduce the risk of conversion to MS after an initial demyelinating event.

[transition music]

And now to our interview with Dr. Timothy Vollmer, Professor of Neurology and Medical Director of the Rocky Mountain MS Center at the University of Colorado in Denver. When we met at the European Committee for Treatment and Research in MS, or ECTRIMS, meeting in Barcelona, Dr. Vollmer laid out how results of the ORATORIO trial of ocrelizumab shed light on two hypotheses of what goes wrong in primary progressive MS, and which one is most likely.

Interviewee – Timothy Vollmer

There currently are two hypotheses for what drives primary progressive disease. One is that it’s like relapsing disease, and it’s driven by inflammation. And the other one is that it’s a noninflammatory disease that’s being driven by neurodegeneration and has a separate biology. Now that we have positive results from the ORATORIO study, which is a study of ocrelizumab which is an anti-CD20 monoclonal antibody that deletes B lymphocytes from circulation, given that this is the very first time we’ve ever succeeded, it’s telling us very important thing, and that is: inflammation does drive primary progressive MS.

And the other important message from here is that this study studied a significantly younger patient population with primary progressive MS than all the other studies. The mean age was around 44. The reason that’s important is because, epidemiologically, we see a decrease in inflammatory activity as a function of age, and older patients often don’t express any evidence of that. And so far, in all the primary progressive studies, especially the OLYMPUS trial, those patient populations don’t respond to anything. So it’s telling us that we can treat primary progressive MS, but you’ve got to start early.

Interviewer – Dan Keller

That seems to be the message overall in MS, in general, though.

Dr. Vollmer

Yes it is. And the reason is, is because MS results in an accelerated brain volume loss, and brain volume loss is going to translate into disability, at some point, for almost everybody. Maintaining brain volume so that you can age normally late in life is a critical goal, not just in MS, but in other neurological diseases.

MSDF

Does that brain volume loss or other changes in the brain relate to really the onset of the progressive phase?

Dr. Vollmer

The answer is yes and no. From a statistical standpoint, it’s very hard to sort of identify a specific point in the process of brain volume loss that you can say, okay, they’re going to transition into progressive disease. That’s probably due to the fact that the mechanisms that underlie reserve capacity in brains may vary a little bit from patient to patient, and that they have different capacity to compensate for this injury. The other complication is that MS, as a multifocal disease, is not necessarily distributed evenly throughout the nervous system, though. In some patients, they have a relatively small amount of disease, but it’s in the neck, and they’re still highly disabled. And because of that very complicated pattern for it, it is hard just to use one global measure to predict how patients are going to be from a disability standpoint.

MSDF

Do the results of the ORATORIO study give us more confidence in pursuing the B cell as an important effector in MS?

Dr. Vollmer

Absolutely. The converging data, now, both in progressive forms and in relapsing forms, says the B cell is playing a critical role. There are CD20-positive T cells, and so there’s still some discussion whether the drug may be having an effect on those, but in the most recent reports, it does decrease those with first administration, but then they recover very quickly. And at subsequent administrations of the anti-CD20, they’re not deleted. So that pattern suggests to me it’s not an effect on T cells, it’s an effect on B cells which remain suppressed for months after a single injection.

MSDF

CD20 is on B cells but, as I understand, not on plasmablasts or plasma cells. So what is the relative contribution of B cell biology versus just antibody?

Dr. Vollmer

A major difference is that plasmablasts and plasma cells are not very good antigen presenting cells. Whereas, B cells, if they can engage the antigen that their B cell receptor is targeted for, become extremely effective antigen presenting cells: the most effective antigen presenting cells in the body. And they can be about ten thousand times more effective that dendritic cells or macrophages. So that’s why I think that, given the fact that the most effective therapies we’ve currently studied right now are all B cell based therapies, I think it’s telling us is that the B cell is playing that critical role, and most likely, that is in both cytokine release and in antigen presentation in the brain.

MSDF

From the ORATORIO study, what more do you want to see? The data is just coming out, and they’re going to do a bunch of analyses. What sort of things should they be looking at?

Dr. Vollmer

Well, they have a number of other clinical measures, and I believe they also have some patient reported outcomes, so I’d be very interested to see if the patients actually perceive a benefit as measured by those PROs. They have the timed twenty-five foot walk out, which they reached and was statistically significant. They had sustained disability progression at both three and six months which was statistically significant. And they reported brain volume loss was decreased in the ocrelizumab treated patients and was statistically significant. We would like to know more about the inflammatory markers in the patients and the correlation between having baseline evidence of disease activity, such as a gadolinium enhancing lesion, and the probability of response to therapy.

MSDF

What about the time course of response to the therapy? It seems like it’s more rapid than you would expect if an insult sometime in the past led to what you see today. But the ocrelizumab results seem to be on a faster track than that.

Dr. Vollmer

Well, the reason I believe that is, is because, as I said before, they really pushed down the median age in their population to much younger patients. And again, in long term studies that have looked at gadolinium enhancing disease activity, we do see it in primary progressive disease. So it’s not true, in my view, that primary progressive MS patients have a different MRI pattern. In studies that actually controlled for observer bias, where the neurologist didn’t have a chance to look with an MRI scan, but made the decision whether it was progressive or not progressive disease based on clinical history, which is the only way that we really can do it, then the previously reported biases of having nonspecific noninflammatory MRIs disappears. And that paper was published about six years ago.

So, I think that we have a lot of built in biases, as a field, when you think about MS, and, unfortunately, those biases are often not supported by objective data. And yet, they do make their way into the literature, mainly because they don’t control for age. And when comparing progressive patients, relapsing patients, or primary progressive patients to relapsing patients the fundamental difference is progressive patients tend to be 10 to 15 years older on average than the relapsing patients they’re comparing them to. And it’s that age difference that explains most of the differences that people talk about. It’s not the fact they have a different form of the disease.

MSDF

Anything else to add on this that we’ve missed?

Dr. Vollmer

As I said, we need to get subset analysis out of the ORATORIO study to see just which age group and demographic the patients really got the most benefit. My suspicion is we’re going to again find it’s the younger patients that show the biggest effect, again emphasizing that starting early in the disease with therapy is a key issue. And, again, I think it’s going to argue that you need to use highly effective therapies as early as possible, in order to get the best effect.

MSDF

Very good, thank you.

Dr. Vollmer

Thank you.

[transition music]

MSDF

Thank you for listening to Episode Fifty-Seven of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Carol Cruzan Morton. Heather McDonald curated the MSDF drug database updates. Msdicovery.org is part of the nonprofit Accelerated Cure Project for multiple sclerosis. Robert McBurney is our President and CEO, and Holly Schmidt is Vice President of Scientific Operations.

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

We’re interested in your opinions. Please join the discussion on one of our online forums or send a comments, criticisms, and suggestions to editor@msdiscovery.org.

For Multiple Sclerosis Discovery, I’m Dan Keller.

[outro music]

Transcript

[intro music]

Host – Dan Keller

Hello, and welcome to Episode Fifty-Six of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.

This week’s podcast features an interview with Dr. Gavin Giovannoni who discusses the first experimental drug to show some benefit in a progressive form of multiple sclerosis in a major trial. The drug is ocrelizumab, and the trial is called ORATORIO. But first, here are some new items in the MS Discovery Forum.

The ocrelizumab findings were the big news at last week’s large international MS meeting in Barcelona, Spain. Our Research Roundup highlights other breaking stories from the meeting. Stay tuned for more in the days to come. We’ll be rolling out in-depth stories on some research themes we followed at the meeting. And we will have some extra meeting-related podcasts for you in the next two weeks.

Every week, MSDF lists the latest scientific papers related to MS, with links to the abstracts on PubMed. Of 138 new studies published last week, we selected three as editor’s picks.

In one study, a British team found a new reason why remyelination fails in disease. When damaged axons lose their myelin sheath, as in multiple sclerosis, they strike up a conversation with immature myelin-making cells. The axons reach out with new synapses to order the cells to grow up and make new myelin. If axons can’t call for help, as also may happen in MS, the myelin-making cells cannot respond. The team made their discovery in rat brains. They also found new synapses and telltale signaling molecules in postmortem brain lesion samples from people with MS.

In another paper, a Spanish group looked at other factors that may block the brain’s ability to repair itself after inflammatory damage. A pair of molecules, known as semaphorins, may block myelin-making cells from coming to the rescue of damaged axons. The findings come from human tissue samples and may hold promise as targets for future treatment.

Our third editor’s pick paper looks at factors influencing the intention to exercise and the execution of exercise among people with multiple sclerosis. A Danish team did an extensive review of rehabilitation and sports medicine literature. They found that health professionals can help on both fronts.

Our Drug-Development Pipeline contains 44 investigational and approved agents for MS. Last week, we added two new findings from clinical trials, we updated information from another trial, and we added 10 other pieces of information to the database. The drugs with important additions are alemtuzumab, dalfampridine, fingolimod, glatiramer acetate, idebenone, natalizumab, and teriflunomide. One update summarizes the finding that fingolimod induces the expression of neuroprotective factors by human astrocytes.

[transition music]

And now to our interview with Dr. Gavin Giovannoni, head of neurology at Barts and The London School of Medicine and Dentistry in the U.K. We spoke with him at the recent European Committee for Treatment and Research in MS, or ECTRIMS, meeting in Barcelona about the Brain Health report that was launched at the meeting and about the ORATORIO trial of ocrelizumab in primary progressive MS. We'll cover the Brain Health report in future podcasts with him and other authors of the report. But today, Dr. Giovannoni lays out the methodology of ORATORIO, which may explain some of the very good reduction in disease progression, observed in this trial for the first time in primary progressive MS.

Interviewer – Dan Keller

In the ORATORIO trial, what was the aim, and I guess what's the big outcome?

Interviewee – Gavin Giovannoni

Well, the ORATORIO trial is essentially a phase III trial of depleting anti-CD20 monoclonal antibody called ocrelizumab in primary-progressive MS. As you're aware, almost every trial done in primary-progressive MS has been negative. And then the motivation behind the ocrelizumab trial was based on the rituximab trial; ocrelizumab is a follow-on and rituximab is more humanized, so that should come with fewer side effects like infusion reactions and anti-drug antibodies. In that rituximab trial, there was a subgroup of the population that responded. These were people that are younger and had MRI activity.

So when we designed the ocrelizumab ORATORIO trial, we tried to enrich the study for young people and people that were more active, more enhancing lesions, and we did that. So the population is younger, and the proportion of patients with gadolinium-enhancing lesions at baseline was about a quarter of them. And we also made sure that all the patients had an abnormal CSF spinal fluid. The reason for that is in the Copaxone glatiramer acetate trial, patients who didn't have an abnormal CSF behaved very differently to those with an abnormal CSF, so we wanted to make sure that we had a homogeneous population. And we made sure they had oligoclonal bands or raised IgG in the spinal fluid simply because we we're trying to target a B cell response; so those that are CSF-negative may not be responsive to a B cell therapy.

Lots of features of this trial that we try to wait to make it positive, so we're really, really excited about the results, that people on ocrelizumab had an approximately 25% reduction in confirmed disease progression on EDSS compared to patients on placebo. And it was an event-driven, so the trial wasn't designed to be a fixed time point, it was designed as soon as you got enough events; it was like an adaptive trial, so it was quite cleverly designed in that regard. So it's great news.

Now whether the trial was positive because ocrelizumab is a more effective therapy than the others, or because it's targeting something special like the B cell, at the moment is not known. The only way we're going to find that out is if we do another primary-progressive trial with another highly effective therapy and see what happens there. But this is fantastic news for people with progressive MS. If you follow any patient forums or blogs or whatever, the most frustrated, depressed group is the primary-progressive patients; they've been neglected for years, decades. I think that's the big news, we now will have a therapy which we can offer them.

The one unknown, though, is maybe this result has been driven by a particular subgroup, and I think the regulators and the payers will want to get that data from us. Because if it is driven by a particular subgroup, they may limit the license and the payment for that particular subgroup, the responder group. And so I can't talk to that yet, because most of the subgroup and post-hoc analyses haven't been done. But potentially maybe like the rituximab trial, there will be a proportion of the patients that have characteristic features that are more responsive to the drug, and drive the trial results compared to the other group. And if that is the case, then it's still good news regardless.

MSDF

As it stands now, it seems like the indication would be for people with abnormal CSF, oligoclonal bands, or elevated IgG. Is there any thought that this drug may work possibly by the same mechanism even if you're not seeing abnormal CSF?

Dr. Giovannoni

The spinal fluid tests aren't 100% perfect, so there are people who will have false-negative results. But I've always been a big proponent of the hypothesis that the oligoclonal response in the spinal fluid is something key to this disease. We see that response in infectious diseases like neurosyphilis, measles, rubella panencephalitis, herpes; it's really a signature of its common to infectious diseases, which is why I'm still a supporter of the hypothesis that MS may be an infectious disease. You do find that in a few other autoimmune diseases, particularly the paraneoplastic plastic syndromes, that it's a signature of an intrathecal B cell response. And this drug targets B cells.

One thing it doesn't target, though, it's the long-lived plasma cell, and so CD20 actually stops being expressed, even on plasmablasts, so as soon as you go from the mature B cell to plasmablast to plasma cells, you don't deplete those with anti-CD20. So we know from rituximab data that the oligoclonal bands persist, so we need longer punctures, you don't get rid of those. But until we have long-term followup, we don't know. Maybe drugs that target the plasmablast and the plasma cell will be more effective than rituximab. We don't have any of those drugs available in MS yet.

There's one that's being developed, it's anti-CD19; CD19 gets expressed onto the plasmablast and some plasma cells, and there are some specific markers for plasma cells. But if you gave those to people with MS, you'd probably deplete them of their antibody-producing cells and make them a gamma globulin anemic. Then you'd have to probably then start supplementing with gamma globulin, so it gets quite complicated. But at the moment, the drug will be licensed, I think, for continuous use every 6 months; it won't be induction therapy. Some of the data would suggest you could potentially use it as induction therapy, so, you know, do 2 years and then wait and see if the disease comes back. But the way the drug's been developed at the moment is for continuous maintenance use. There are some concerns; can you continue to use it in the B cell depletion forever? And that's going to have to be answered with the open-label extension studies.

MSDF

Since plasma cells persist and oligoclonal bands persist, if I understood you correctly, do you think that the pathology is mediated through antibody, or this depletion of B cells is acting in a different way, that the B cells are interacting either with T cells or on their own doing something?

Dr. Giovannoni

I mean, there is pretty good evidence from the pathology literature that antibodies are very important in MS. So whether or not you accept it, there is pathological classifications of the top 1 to 4. And there is antibody and complement activation in MS lesions, and there is emerging evidence that so-called grey matter lesions and subpial lesions on the surface are particularly driven by antibody and complement. So I do think they are pathogenic. And so you may get rid of the focal inflammatory lesions that appear to be T cell-driven, whereas the cortical subpial lesions may be antibody-driven. So you may be getting rid of one pathology and not all the pathologies, which is why I remain a little bit skeptical still about whether or not this anti-CD20-depleting antibody will be effective in the long-term. So we may need additional treatment to target plasma cells.

And what you've got to ask yourself really is what's driving those oligoclonal bands. We know they are highly selected, so they're not just there. They're oligoclonal, they've undergone selection by hypermutation, so there's some antigen driving them. They respond to something, and we just haven't been able to find out what they respond to. They are pathogenic, and if we do find the cause of MS, that will almost certainly begins to cause the disease. An analogy would be herpes encephalitis; if somebody's had a herpes infection, then you take those oligoclonal bands out and you absorb them against the antigen from herpes, you remove almost all the antibodies. So they are antigen-specific in the infectious space.

We've tried for years to find out what those bands react against in MS, and we haven't found it. There's several groups still working on it, and I would encourage them to continue working it, because that may be where the action is.

MSDF

The ORATORIO data was only begun to be analyzed very recently. You had mentioned that you were going to be doing subgroup analyses. Are there other analyses yet to come?

Dr. Giovannoni

I mean, the headline results are probably in main secondary outcomes, and there's less of tertiary outcomes. We need to do subgroup analyses trying to look at brain atrophy, the time course of the progressions. I'm very interested in second progressions, because I have this theory that early progressions in progressive disease is not driven by inflammation that occurs in this epoch, it's in the past; so inflammation a year or two ago is driving progression now. And so when you design these progressive trials, a large number of people progress early. And I think it's nothing to do with the trials because it's happened before the trial. So what you then need to do is look at progressions in the future to see if they flatline or stabilize. So there's lots of luck. I think we need to play around with the data, look at the first and second confirmed progressions, incorporate the brain MRI activity as the confounder. There's lots to do, tons to do. But it's good news. The excitement about those analyses are generated because you've got a positive result.

MSDF

Picking up on this idea that what you see today is the result of an insult that happened sometime before, what is the time course that you see using ocrelizumab in terms of benefit; is it so rapid that it questions whether what you said is what's operating?

Dr. Giovannoni

Yes, it's too rapid. When you see the survival curves, they go flat very early, so this is actually saying something else which is really surprising me, which is why I think some of the activity may be driven by an anti-inflammatory, because we know that anti-inflammatory drugs have an effect quite quickly. So that's why I'm suspicious that the positive result is driven by an inflammatory core of patients, and those with the more neurodegenerative or previous inflammation are unlikely to respond. That's my worry with the drug. But let's see what their subgroup analyses show.

MSDF

Anything we've missed or important to add on that?

Dr. Giovannoni

What I want to mention to people with the disease is they shouldn't overhype expectations. The simple reason is when you've got progressive disease you've already lost reserve, so that's why you're progressing. So in early relapsing disease, you make recovery from attacks because you've got ability to recover, a reserve. And so early on you stabilize or improve, and later on you slow down progression. So I'm trying to tell people with the disease if you do go into this therapy, don't expect to improve or get better. You're much more likely to progress more slowly, which you won't notice. It's hard in an individual to say they're progressing more slowly, or you'll plateau out and stabilize. I think that must be the expectation, rather than improvement. And I think we need to manage those expectations, that people may not at a personal level find a big dramatic response in terms of their disability on the drug.

MSDF

But this sounds like – getting back to the discussion of the Brain Health report – where you should diagnosis and treat rather quickly. At least now if someone comes in with primary-progressive, there may be at some point something to do from the start.

Dr. Giovannoni

Yeah. Well, it's like with any neurodegenerative disease, the sooner you treat the more you've got to protect, and the later you treat the less you've got to protect. So this would be a call to get primary-progressive disease diagnosed as soon as possible and treat as soon as possible. And if you look at the diagnostic delay in primary-progressive disease, it's probably worse than relapsing disease. People often go years before being diagnosed. So we're going to have to sharpen up the referral pathways and the diagnostic pathways in primary-progressive disease to get that timeless brain concept across there, too.

[transition music]

Thank you for listening to Episode Fifty-Six of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Carol Cruzan Morton. Heather McDonald curated the MSDF drug database updates. Msdiscovery.org is part of the nonprofit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is Vice President of Scientific Operations.

MSDiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

For Multiple Sclerosis Discovery, I'm Dan Keller.

[outro music]

[intro music]

Host – Dan Keller

Hello, and welcome to Episode Fifty-Five of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.

This week’s Podcast features an interview with Dr. Michael Levy, who discusses the status of regenerative stem cell therapies for multiple sclerosis. But first, here are some new items in the MS Discovery Forum.

Our lead story last week looked at a way to prevent a rare but dangerous viral brain infection that can be a side effect of certain drugs. The risk of infection limits the people who can take natalizumab to prevent the inflammatory brain attacks of relapsing-remitting MS. Two new papers propose vaccinating people against the virus. Experts are still debating the underlying biology, but they say the approach should be tested in people.

Every week, MSDF lists the latest scientific papers related to MS, with links to the abstracts on PubMed. Of more than 100 new studies published last week, we selected three as editor’s picks.

One study comes from the Italian registry of pediatric MS patients treated with natalizumab. Researchers evaluated 101 boys and girls. Natalizumab was safe, well tolerated, and effective, they report. Time on the drug varied, but the overall mean was about three years. Most of the patients switched because of a poor response to first-line drugs, such as interferon-beta and glatiramer acetate. The patients’ sera were assessed for anti-JC virus antibodies to prevent the rare but dangerous brain infection associated with natalizumab.

Two other studies caught our eye this week. One goes into the new insights from live imaging in the central nervous systems of mice. The authors outline potential applications that could lead to therapies to protect or restore myelin. Another study asked if spasticity of lower limbs could be helped with anodal transcranial direct current stimulation in 20 MS patients. The answer is no, based on the results of the small randomized double-blind clinical trial. This is not to be confused with another noninvasive technique that seems to reduce spasticity, called transcranial magnetic stimulation.

Our Drug-Development Pipeline contains 44 investigational and approved agents for MS. Last week, we added an extensive meta-analysis of clinical trials, we updated information on three trials, and we added 16 other pieces of information. The drugs with important additions are alemtuzumab, daclizumab, dimethyl fumarate, fingolimod, glatiramer acetate, GNbAC1, interferon beta-1a, interferon beta-1b, laquinimod, mitoxantrone, natalizumab, ocrelizumab, and teriflunomide.

One update reflects the finding that ocrelizumab slows disease progression in primary progressive MS, the first drug to do so, as described in the drug-maker’s news release. Another update reflects a meta-analysis by the Cochrane Multiple Sclerosis group. It compares 39 different clinical trials involving more than 25,000 patients to rank benefits and acceptability of 15 different MS drugs. Doctors and patients need even better information to make decisions, the authors conclude. They call for more randomized studies directly comparing active agents, no more placebo-controlled studies, and long-term followup of all drug studies.

The MSDF team is attending this week’s ECTRIMS meeting in Barcelona, Spain. If you, too, will be at the conference and would like to meet with us – or if you’re interested in being interviewed about your research for a future podcast – please email us at editor@msdiscovery.org.

[transition music]

And now to our interview with Dr. Michael Levy, assistant professor of neurology at Johns Hopkins University. We met in his office to talk about stem cell regenerative therapies – what the aims are and where things stand.

Interviewer – Dan Keller

Let's talk about regenerative stem cell therapies, but I suppose the first thing to make clear is nothing is approved yet, is that right?

Interviewee – Michael Levy

Nothing is even closed to being approved. There are many trials in progress in multiple sclerosis and in spinal cord injury, which is a related demyelinating condition in which stem cells are being tested, and this is worldwide, probably over 20 studies that are ongoing.

MSDF

What are some of the goals?

Dr. Levy

The goals are twofold. In multiple sclerosis in particular, the two goals are to recover function and to neuroprotect against future insults. So in spinal cord injury, for example, there's only one goal which is recovery of function, because they don't have to worry about future insults.

MSDF

Now no one really has the exact idea, or I guess there's many ideas, of how these would work – whether the cells would actually replace lost cells, whether there's secreted trophic factors – so are people looking at them specifically in those areas, or whatever works at this time, then they'll figure out why?

Dr. Levy

It certainly started off with the mechanism in mind that the cells would replace lost tissue. That was really how things started. But as they've evolved, patients have responded in part to many different types of stem cell therapies, and none of them have involved replacing lost tissue. And so there are probably many different mechanisms involved, and it's evolved into exactly what you've described, a phenomenon of wow, this really works, let's continue it and let's try to figure out what's going on in parallel.

MSDF

Is there also a thought that the stem cells really are just providing a supportive environment, or even a supportive structure, for natural processes to proceed if they have the right setting?

Dr. Levy

Oh, sure. There are some studies where the stem cells only survive, or are only around, detectable, for about one hour, and then beyond that they can't be detected, but yet they provide some significant long-lasting benefits. So exactly how they do that is not clear.

MSDF

Are you familiar with the mouse experiments of Jeanne Loring at Scripps; she had taken human pluripotent stem cells in a mouse model and they were gone after a week, but then the mice got up and walked around and seemed to look perfectly normal.

Dr. Levy

So definitely mouse models have recapitulated what we've seen in humans, which is that the stem cells provide some sort of benefit. Whether it's secretion of trophic factors, or neuroprotection or replacement of tissue, or what they call neural bridging, allowing neurons to communicate through in the alternative circuit, this is true in mice, too. So whatever is happening in humans is probably also going on in these mice.

MSDF

Specifically in the MS area, what are people or companies doing?

Dr. Levy

Specifically in MS, the most common trial that's being conducted now is testing mesenchymal stem cells--taking them from that patient, usually from the hip, purifying them in the lab, and then injecting them back into the patient, either into the bloodstream or into the spinal fluid. Initially, the goal was to try to replace lost tissue, but now the goal has evolved, and what these studies are really looking for is sort of the 6-month or 12-month outcome to see if patients recover better, have fewer relapses, and better outcomes.

MSDF

Now mesenchymal stem cells in themselves are not going to turn into the lost kinds of cells you really want to replace, but they do have immunomodulatory effects, is that right?

Dr. Levy

That's the thought. So mesenchymal stem cells are all the cells in the bone marrow that don't turn into blood cells, either red or white blood cells; it's the rest of the matrix. And in the lab, you can turn them into neuronal cells and supportive cells that you find in the brain, but that doesn't happen when you put them into spinal cord or brain; they don't tend to differentiate into neural tissue. And so they are doing something else, and part of that is probably neuromodulatory. Correct.

MSDF

Besides mesenchymal stem cells, people are looking at a little more differentiated cells, oligodendroglial precursor cells--you obviously want to remyelinate. Do you have an idea of what's going on with those and has there been success there?

Dr. Levy

So all the studies using neural stem cells and neuroglial stem cells are currently being conducted in spinal cord injury. And in spinal cord injury there is a component of demyelination, and they're hoping that those oligos migrate to that area that is demyelinated and that it will remyelinate the lesion. So all MS patients should keep an eye on those studies to see how those turn out.

MSDF

The difference there is you can identify an area of lesion. In the brain, you don't know exactly where lesions are going to come up, and lesions disappear also.

Dr. Levy

MS patients tend to have dozens of lesions, and many could be in the same pathway. So even if you remyelinate one, there could be one upstream or downstream of that lesion that's still impairing the function. In spinal cord injury, there is just one lesion, and they're trying to remyelinate just that one; you're correct about that.

MSDF

Are you familiar with the work by Basil Sharrack in England? There were about 10 patients, I think. They did myeloablative therapy and autologous bone marrow transplants, essentially as they called it, rebooting the immune system. That's obviously a stem cell therapy in a sense.

Dr. Levy

Absolutely, it is a stem cell therapy. The thought there is – exactly like you said – rebooting the immune system; taking out only the most immature stem cells that haven't been exposed to whatever the trigger of their disease was, taking those stem cells out and sparing them, holding them in the lab, then getting rid of the rest of the immune system in the patient's body and reintroducing those stem cells back; as you said, rebooting the immune system to see if we could return their immune system back to the pre-MS state and see if that has a better outcome. And, generally, those types of studies where we're really ablating the immune system have tended to have good outcomes; some patients are able to come off of therapy for years, but ultimately the disease comes back. And it could be years; it could be five, even up to ten years. And so we really have to understand why that is. If there's another environmental exposure or if there is just something really genetically encoded into the immune cells.

MSDF

Or, for example, if there's an EBV etiology, the Epstein-Barr virus is still there probably

Dr. Levy

That's right, so EBV may be that environmental trigger.

MSDF

One thing I don't understand about that is they reported, I think, in Science Translational Medicine, that people who had pretty significant disability – you know, using a wheelchair – could then walk again. It seems rebooting the immune system should not do anything to reverse or restore neural function.

Dr. Levy That would be my expectation, too. So in any study where we're looking at effects on the immune system, I wouldn't expect the nervous system to have such a dramatic recovery either. That was a surprise.

MSDF

What else is there to say about stem cell therapy's messages to physicians who are asked about it, messages to patients who are interested in it at this point?

Dr. Levy

At this point, I would say that the verdict is still out, that the studies need to be completed, and that there are a lot of companies out there offering "stem cell therapies" to patients with MS, who are just looking for anything to improve their function. And that can be dangerous, because we don't really understand this science works, and there have been some bad outcomes reported in the literature from patients who are seeking this type of care from clinics offering "stem cell therapies." And I would just caution patients and caution doctors to wait until these studies are done and we have a better sense of how they work.

MSDF

There seems to be a lot of fly-by-night operations on the internet and overseas, and things like that, but even with legitimate trials I would guess there could be bad outcomes. What sorts of dangers are there in stem cell therapy?

Dr. Levy

There are two. One is that the stem cells will develop into tumors, because these stem cells are now able to proliferate, that's one of their features. So a concern is that they're going to proliferate uncontrollably into a tumor. And the second concern is that you're reintroducing a foreign cell – in some of the trials they're foreign cells – and that might trigger a relapse. So if you inject it directly into the spinal cord, could you then cause another inflammatory event in the spinal cord targeting those stem cells? So those are the two major concerns.

MSDF

Is there anything important to add, or that we've missed?

Dr. Levy

No, I would say that pretty much covers it.

MSDF

Well, thank you.

[transition music]

Thank you for listening to Episode 55 of Multiple Sclerosis Discovery. This Podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Carol Cruzan Morton. Heather McDonald curated the MSDF drug database updates. MSDiscovery.org is part of the nonprofit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our president and CEO, and Hollie Schmidt is vice president of scientific operations.

MSDiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

For Multiple Sclerosis Discovery, I'm Dan Keller.

[outro music]

Transcript will be available Friday, Oct  2

[intro music]Host – Dan KellerHello, and welcome to Episode Fifty-Three of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.This week’s podcast features Dr. Jonathan Kipnis, who discusses his recent discovery of lymphatic vessels in the meninges. But first, here are some new items in the MS Discovery Forum.According to our curated list of the latest scientific articles related to MS, 34 such articles were published between August 21st and 28th. To see these publications and the articles we selected as Editors Picks, go to msdiscovery.org and click on Papers. Our Drug-Development Pipeline includes continually updated information on 44 investigational agents for MS. This week, we’ve added 6 pieces of information about alemtuzumab and fingolimod. To find information on all 44 compounds, visit msdiscovery.org and click first on Research Resources and then on Drug-Development Pipeline.The MSDF team is looking forward to attending next month’s ECTRIMS meeting in Barcelona, Spain. If you, too, will be at the conference and would like to meet with us – or if you’re interested in being interviewed about your research for a future podcast – please email us at editor@msdiscovery.org.[transition music]And now to Part 1 of our interview with Dr. Jonathan Kipnis, Professor of Neuroscience and Director of the Center for Brain Immunology and Glia at the University of Virginia in Charlottesville. His group recently published in Nature their discovery and characterization of lymphatic vessels in the meninges. Interviewer – Dan KellerYou've described in this paper about meningeal lymphatics, the novel but actually more conventional path for cerebrospinal fluid drainage from the CNS than I guess had been thought of before; it's sort of conventional as revolutionary. Can you tell me what you found and what led you to look?Interviewee – Jonathan KipnisYes, so we've been interested in the role of meningeal immune system for quite some time, and we've shown that changes in meningeal immunity could impact brain after a CNS injury, or also for normal brain function. So, for example, mice that have impaired meningeal immunity would show cognitive deficits and would show some little bit more prone to stress and other phenotypes. So we've been very interested in understanding how meningeal immunity is being regulated. So the assumption was at some point that there is no immune cells in the brain, which is true, except for microglial which reside in the brain and compose 10% of the brain cells, but there is no peripheral immune cells within the brain. But in very nearby areas, which is the surroundings of the brain – the choroid plexus, the meninges, and the CSF – that's where actually there are immune cells, and there are all types of immune cells. And so we have been very interested to understand how the cells are getting in and getting out. Through the use of parabiotic mice, we demonstrated last year, we showed that immune population of the meninges is not static; the cells are being repopulated, and about 50% of T cells, for example, is being exchanged within about 10 days, and major exchange between the CSF or the meninges with the deep cervical lymph nodes. So nothing was really new, we just sort of established things maybe more solid way. Those cells can get in while still nobody understands very well how they get in; we'll assume they get in through the meningeal vasculature, which is probably true. But then how do they get out, or what happens with cells after they get to the CNS? Well, the assumptions were, well, they either die, magically disappear, or crawl under the nose through the cribriform plate and into the deep cervical lymph nodes through the nasal mucosa. They were okay explanations, but in our systems we did not find any of it to be sufficiently explaining what's going on in this really fast and pretty dramatic exchange of the immune system within the meningeal spaces. So when we just looking at it a bit closer, and it is very, very well established that there is lymphatic drainage from the CNS, so this needs to be remembered. So people in many labs have shown that if you put stuff in the brain – which stuff I mean proteins – if you put proteins or antigens in the brain, whether it's in the parenchyma or in the meninges or in the CSF, you will find those proteins, and you will find immune response to these proteins in the deep cervical lymph nodes.The question is, of course, how do they get there? And the path which was described just did not work in our hands, and so I was lucky to get a very, very talented postdoc, Antoine Louveau, at the lab. He realized that for us to understand how things get in and out, the only way to do it is to do live imaging and also to do a whole mount of the entire meninges. And I think that's when it was a breakthrough point. So Antoine laid out the entire meninges and was looking for location of the immune cells. And he said let's see where I see maximum accumulation of the immune cells, and then let's see how these places will change when we expose mouse to, for example, stress, learning, or EAE inflammation, viral infection, or whatever, let's see how these areas of dense immune population will change. And so he realized that there is a lot of immune activity around the major sinuses in the meninges, and then he saw that there are immune cells which are in the vascular structures which were not blood vessels. And I think that was the turning point. And I said, okay, if the cells are within the vasculature which is not blood vasculature, what would it be? Well, so I went to colleagues here and said what do you label lymphatic vessels with? And they didn't understand why would you want to label for lymphatic vessels, because they don't work with the brain. And so we labeled a lymphatic marker and we saw the vessels, which were lining the major sinuses and going all the way along them. So that's a very long answer to your very simple question.MSDFAnd Antoine Louveau's technique here that was the key to it was doing in situ fixation so he could get the meninges out intact?Dr. KipnisTo let's assume the meninges came out intact on the brain, and let's assume we had this beautiful staining. Let's say we did the coronal staining, and let's say we're labeling for lymphatic vessels. So you can imagine that what you'll see is at the border of the brain you will see a dot; you will see maybe three dots because there are three vessels going along the sinuses. And when you see a dot, you never take a dot seriously in immunohistochemistry. Now that we know that this dot represents the vessel, then we can actually go back and do those coronal sections and look at it. But back then only by seeing the whole meninges mounted as one on a slide, and by seeing those vessels there, I mean that's when we knew. And so to us it was obvious this is something that absolutely went under-noticed. And this technique of whole-mount meninges, I think, was absolutely crucial. MSDFDid he find these vessels in all layers of the meninges, or any specific ones?Dr. KipnisNo, no. Major lymphatic vessels are following the superior sagittal and the transverse sinuses, which is in the dura. So all the blood from the brain is being – at least in mice. In humans it goes a little bit different, but also through the sinuses, although sinuses are located so not all the blood in the human brain goes through the parasagittal sinus, but in the mouse brain all the blood goes through the sinuses in the dura. So major sinuses through which all the blood is being collected from the brain, and then goes out there. And so along those sinuses we find the lymphatic vessels, so they are sitting in the dura. MSDFAnd this system also has been found in humans?Dr. KipnisWell, that's a good question. You know, it's very hard to obtain high-quality human samples from the dura, because nobody really cares about this area. So we were lucky in the triple operation of Bea Lopes, who's a really great neuropathologist here at UV; she was able to give us, I think, nine samples from patients of dura of the sinus; these were all fixed in formalin. So we looked at those, and as you can imagine, the sinus in the human is huge, so obviously compared to a mouse. So in two out of nine, we were able to identify vessels that looked like meningeal vessels, but I think it warrants much deeper and much farther investigation to be able to say, yes, here they are. But if you ask me personally, why wouldn't they be? Why would mice have them and humans won't have them. So I think it's a matter of identifying their location and the best markers to use for them, but I think they should be there again. In two out of the nine samples, we were able to demonstrate that this is something that looks very, very good. MSDFAnd you did immunohistochemistry on these to show the lymphatic properties and not general blood circulatory vasculature properties, either in the mice or human?Dr. KipnisOh, yes. So in the mice we identified the characteristics of those vessels really, really well. You know, nothing is perfect, that every marker on mouse markers are expressed by different cells, so you need here to provide a series of markers and to demonstrate that this is also indeed the real lymphatic cells. So we stained for LYVE1 and we showed beautiful staining with LYVE1, also with macrophages. And those are vascular structures and they came out to be macrophages. But one of the major transcription factors that will define lymphatic and endothelial cells is a Prox1. So we demonstrated two ways of Prox1; one is transgenic mouse and the other is staining for Prox1. And we also did two other molecules. One is a Podoplanin which is expressed in tissue lymphatics, and these vessels are expressive. And the other molecule, she is very interesting. It's a receptor for VEGF3, VEGF-C. And this receptor is first on the lymphatic and endothelial cells. In the periphery, lymphatic and endothelial cells will respond to recombinant VEGF-C and will expand. So what we did here, we also injected a recombinant VEGF-C and we showed these vessels expanding. So we know now that the receptor is actually functional in the vessels, but also we now can expand the vessels. Whether it will impact any neurological disease, we don't know, but at least we have the capability to do so. And then we also identified them by flow cytometry. We took samples from skin and from diaphragm where lymphatics are very, very well defined, and using the exact same antibodies we did also flow cytometry on our meningeal samples. And we show that the cells look exactly like they look from the skin and from the diaphragm; of course, the numbers are much smaller. So I think in terms of their calculation in a mouse, we are very convinced.Now for humans it's more difficult. Like I said, the sample was in formalin and it's very hard to work with those samples, and, again, the area is huge to go through. So we were able in humans to get two markers to work; one was LYVE1 and the other was Podoplanin. We could not make Prox1 to work, I think it's a problem with the antibody and not with the vessel or potentially with the tissue as well. And these vessels would not label for some other markers, which would be characteristic of, for example, macrophages. So we were able to attack on them two out of four markers that would potentially allow for him to see. But we are now trying to identify those vessels by other means in humans as well, and I think flow cytometry may be the way to go. MSDFNow you've shown that these lymphatic vessels drain into the deep cervical lymph nodes, and it looks like you've also been able to rule out drainage through the cribriform plate back into the cervical lymph nodes. Is that true? Dr. KipnisI'm glad you bring this up, this is very important. So if you think of CSF, CSF is composed of several things. So we have the liquid itself, we have the macromolecules within the CSF, and then we have the immune cells within the CSF. So I don't think there is anybody would argue against liquid being drained through the cribriform plate and through the granulation; this is funny to argue. And obviously we are not claiming anything until we're absolutely sure; there is beautiful works from many, many labs showing that. But for the macromolecules and for the immune cells, the path which was proposed through the cribriform plate most probably if it's not a wrong one, it's probably not the major one. [transition music]Thank you for listening to Episode Fifty-Three of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is vice president of scientific operations. Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.[outro music]

[intro music]Host – Dan Keller Hello, and welcome to Episode Fifty-Two of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.This week’s podcast features Dr. David Tabby, who discusses the incidence of headache in MS. But first, here are some new items in the MS Discovery Forum.According to our curated list of the latest scientific articles related to MS, 53 such articles were published between August 14 and 21. To see these publications and the articles we selected as Editors Picks, go to msdiscovery.org and click on Papers. We’ve made some recent updates to our Funding Opportunities and our Meetings and Events listings, both of which can be found under our Professional Resources tab. Be sure to take a look at a newly-posted funding announcement entitled, “National MS Society: Health Care Delivery and Policy Research Contracts.” If you know of any meetings, events, or funding opportunities that are missing from our lists, please email us at editor@msdiscovery.org so that we can include them. Our Drug-Development Pipeline includes continually updated information on 44 investigational agents for MS. This past week, we’ve added one new trial and 15 other pieces of information. The drugs with important additions are dimethyl fumarate, fingolimod, glatiramer acetate, interferon beta-1a, interferon beta-1b, and ofatumumab. To find information on all 44 compounds, visit msdiscovery.org and click first on Research Resources and then on Drug-Development Pipeline. [transition music]And now to the interview. Dr. David Tabby is an adult general practice neurologist, with a subspecialty in multiple sclerosis, in Bala Cynwyd, Pennsylvania. He was formerly associated with Drexel University College of Medicine in Philadelphia where he carried out the study on headache and MS that we discussed.Interviewer – Dan Keller Could you just tell me what the aim was? I think you were looking the variables affecting headache occurrence in MS patients.Interviewee – David Tabby Well, to be perfectly frank about that, my business manager had noted that many of my MS patients also had migraine, and she asked what’s going on with that. So we did a cursory review and found that close to 50% of my MS patients also had migraine. So that prompted the survey in a more formal fashion.MSDFWhom did you look at, and what were some of the variables you looked at?Dr. TabbyWell, we looked at everyone who was willing to answer a survey. And we wanted to include some typical migraine variables like frequency and intensity and triggers and age of onset and duration at that time and which came first, MS or migraine.MSDFAnd what were some of the major findings?Dr. TabbyI think our biggest contribution was that it seemed that we could correlate exacerbations with increase in headache, which I don’t think was known before that. Sometimes headache a little bit before the exacerbation, and sometimes exacerbation first, then with headache. But that raised the question about the role of inflammation in both headache and MS exacerbations. You know, I don’t think one is the cause of the other, but they’re clearly related.MSDFWhat about migraine with aura or without? Are there differences in the MS presentations or symptoms or relations in time?Dr. TabbyWe didn’t have a lot of migraine with aura patients. That’s only about 20% of the migraine population anyway. We didn’t have a big enough number to make any kind of association that would be distinguishing migraine with or the migraine without aura.MSDFDo you have a proposed mechanism in mind how these two may be linked – mechanism of migraine, mechanism of MS?Dr. TabbyI don’t think there’s a lot of work about what the immune system’s role is in migraine, but stress affects the immune system. My patients tell me that a particularly stressful event can seem to precipitate an exacerbation, and, no big secret, that stress can precipitate a migraine.MSDFFatigue can be a trigger, and obviously, that’s a large proportion of MS patients have it. So do you think there may be a link there, one triggering the other?Dr. Tabby90% of MS patients will complain of fatigue at some point, and I think that’s clearly got something to do with it. So anyone with migraine will tell you that when they overdo it and get overtired, they get a migraine.Interviewer – Dan KellerI think I saw something in the paper was talking about metalloproteinases in the CNS and leakiness of vessels and allowing either antigens out or T cells in. Does that have any legs or where does that idea come from?Dr. TabbyThat idea came from a paper that we found in our literature review of the basic pathophysiology of an MS exacerbation that matrix metalloproteinases have to be activated first, to increase vascular permeability of the CNS. Migraine was thought, at one time, to be a primarily vascular issue. It’s not. It’s primarily a neurochemical issue that affects the vasculature, but results in dramatic changes in blood vessel permeability. There’s a kind of leakage of fluid around blood vessels, which helps make them more sensitive.MSDFThere’s also a component of calcium flux in migraine. Would that have any effect on the immune system? There’s calcineurin inhibitors that are immunosuppressants, so I’m wondering if calcium in itself – could be an imbalance be a stimulant?Dr. TabbyThe role of calcium in modulating neural function can’t be overstated. I’m not ready to give you an exact mechanism of how that might function.MSDFPatients with migraine supposedly have more symptomatic clinical course of MS. Do you have any numbers there? What did you find?Dr. TabbyWe weren’t a longitudinal study. We’re really just a snapshot kind of picture to determine, you know, a relationship now. That was another one of our hypotheses that the worse headache you had the worse MS you were going to have. Our take-home message from the paper was MS doctors should be very aggressive about addressing migraine symptoms in their patients, because we think that it could have an effect in long-term prognosis in MS. And it’s not just the patient complaining about, oh, I have a really bad headache. There is a relationship. It’s been known for many years. I mean, you might have seen in our bibliography that some of the papers went back to the 1960s about the relationship with headache and MS. So, just to reiterate, migraine prophylactic therapy, migraine abortive therapy is important in the context of treating MS.MSDFCan pre-existing migraine before the MS diagnosis give you any clue as to being a risk factor in itself?Dr. TabbyThat’s an excellent point. We didn’t have a big enough group to come to that conclusion, but 12% of Americans have migraine – 18% of women, 6% of men. Less than 1% of the population has MS. Something else has to be happening.MSDFAlso, I guess you found that people with stabbing pain had more acute MS exacerbations than if they had other more throbbing kinds of pain.Dr. TabbyWell, we were just using that as an indicator of severity of the headache. Stabbing’s not a typical word used to describe migraine. We gave choices. We just didn’t leave it open-ended. We gave some example words for their responses to the survey to tick off. Yes, stabbing was one of them, and there was a correlation between the ones who said stabbing and worse exacerbation.MSDFSome of the patients you surveyed did not have pre-existing migraine, only after their MS diagnosis. Do you think that migraine is something that one should investigate whether they actually may be in a prodrome of MS, if they present late - develop migraine late in life – later in life?Dr. TabbyIn our world, pretty much everyone with a bad headache who sees a doctor about it, at some point is going to get some sort of imaging study of the brain. It might be a CAT scan, in which case there might not be enough information. But if it’s an MRI, there’s a good chance of seeing high-signal lesions scattered through the white matter. They may be real small and not particularly typical of MS. But not uncommonly, they’ll see a pattern that looks really quite like MS. And you examine the patient, and you don’t find anything that’s consistent with MS. You do a history, and you don’t find any symptoms that are consistent with MS. So this is the sort of thing you just file away and see what happens. I don’t think anyone would suggest that treatment for MS should be started at that point. There’s an entity that’s finally gotten a name, called radiologically isolated syndrome, which people get MRIs of their brain for some reason – head trauma, headache, anything really – and the pattern looks really quite like MS, but there’s no clinical support of MS. So same thing; we don’t forget about these people. You recheck their MRIs at some point in the future. You look for new lesions or enhancing lesions. I think the latest statistic is somewhere around 50% of them are eventually going to present as having multiple sclerosis.MSDFWould each entity be treated or each condition be treated as if it existed in isolation? Or do they complicate the management of the other?Dr. TabbyMy approach has been to treat them independently. Just follow the basic principles of headache treatment for the headache and the basic principles for MS treatment and adjustments of therapy and symptomatic therapy for MS. I would not suggest some interlinked therapy system.MSDFBut something like interferon and possibly other drugs may cause exacerbation of headache. Would that lead to noncompliance of the MS treatment or would you switch drugs or how do you handle that?Dr. TabbyThat doesn’t necessarily involve the headache issue. I think someone who has bad headaches on interferon who’s not taking their medicine, you know, you might try to fix it – fix the headache that is. But you’re probably fighting an uphill battle when that patient has negative associations with taking their medicine. I still tend to think of these two things as related but separate.MSDFSo what’s the big take-home message for a physician?Dr. TabbyReally just about treating migraine aggressively in their MS patients, and keeping in mind that we work very hard to preserve function to reduce the accumulation of disability, with drugs and other sorts of interventions. But intervening for migraine may be just one other way to reduce the burden of disability in the future, for your patients.[transition music]MSDFThank you for listening to Episode Fifty-Two of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is vice president of scientific operations. Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org. [outro music]

[intro music]

Host – Dan Keller

Hello, and welcome to Episode Fifty-One of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.

This week’s podcast features Dr. Luke Lairson of Scripps Research Institute, who discusses discovery of small molecules to induce remyelination and, in particular, some muscarinic receptor antagonists currently approved for other indications. But first, here are some new items in the MS Discovery Forum.

According to our curated list of the latest scientific articles related to MS, 114 such articles were published in the first two weeks of August. We selected a few of these articles as our Editor’s Picks. One is a longitudinal study of gray matter lesions and cortical atrophy in MS published in PLOS ONE. The investigators obtained MRIs at baseline and five years later from subjects with clinically isolated syndrome, early and late relapsing-remitting MS, and secondary progressive MS, and examined lesion placement and cortical thinning in the different disease subtypes. To see this publication and the other articles we selected, go to msdiscovery.org and click on Papers.

Our Drug-Development Pipeline includes continually updated information on 44 investigational agents for MS. During the past week, we added 1 new trial, we updated information on 2 other trials, and we added 12 other pieces of information. The drugs with important additions and changes are ATX-MS-1467, daclizumab, dimethyl fumarate, fingolimod, glatiramer acetate, interferon beta-1a, and interferon beta-1b. To find information on all 44 compounds, visit msdiscovery.org and click first on Research Resources and then on Drug-Development Pipeline.

[transition music]

And now to the interview. Dr. Luke Lairson is an assistant professor at the Scripps Research Institute and a principal investigator at Calibr, the California Institute for Biomedical Research, in La Jolla. We spoke at the research institute.

Interviewer – Dan Keller

Dr. Lairson, we're talking about the potential for remyelination. And your institution is taking a very systematic and maybe novel approach. Can you describe how you're going about looking at possible ways to induce remyelination?

Interviewee – Luke Lairson

Sure. So we're using a phenotypic assays to look for small molecules that selectively induce the differentiation of the precursor cell population which is required for remyelination, which are the so called oligodendrocyte precursor cells or OPCs. We developed imaging-based assays where we could look for small molecules that selectively induce that differentiation phenotype.

MSDF

And how are you going about screening compounds, and what is your institute set up to do?

Dr. Lairson

So at Scripps and Calibr we have the capacity to screen on a million compound scale capacity to look at molecules. In this particular assay, we do it in a 3D four-well format, which limits us to screening collections on the scale of hundreds of thousands. And to date, we've screened about 200,000 compounds with this assay.

MSDF

In terms of multiple sclerosis, what are you looking at now?

Dr. Lairson

From our preliminary screen of our collection of bioactive compounds, including FDA-approved drugs and drugs in late-stage clinical development, we identified a series of compounds for which OPC differentiation had not been previously reported, which are muscarinic receptor antagonists, which are clinically approved drugs and which work in the central nervous system. And we demonstrated a number of these compounds work in two different rodent models of remyelination in MS. And we're currently developing these as a lead class of compounds as a combination therapy when combined with existing immunosuppressant drugs, including Gilenya.

MSDF

What compounds have you focused on most? There's a multitude of approved antimuscarinic agents.

Dr. Lairson

Right. So this is actually a a critical point. So we identified a number of compounds which had antimuscarinic activity, which were active in our OPC differentiation assay. We used pharmacology to demonstrate that the antagonism of M1 or M3 receptor subtype is a required component of the mechanism of these drugs. However, we think that there's a second target, and it's a dual mechanism action through which these drugs are acting, which we're currently trying to elucidate what that second target is to fully characterize the mechanism. That second target actually provides the opportunity to identify compounds that have a potential to have a better therapeutic index in vivo. So the lead compound we published was benztropine. Jonah Chan's lab at UCSF later showed that clemastine also works, which was in our paper, as well. So these are drugs that have been demonstrated to work in vivo.

What we did after we published that is we then looked at every compound that we could get our hands on that had antimuscarinic activity – specifically targeting M1/M3 receptor subtypes – and then characterized their activity in the OPC differentiation assay and, as well as profiling their potency on the M1/M3 receptor subtypes, with the goal of looking for compounds that have an optimal therapeutic index in terms of on-target toxicity. So benztropine induces OPC differentiation in the low micromolar range, but it antagonizes M1 and M3 receptors in the low nanomolar range so there's a discrepancy there. And we think that the on-target toxicity of antimuscarinic activity is going to limit the therapeutic potential of these drugs. We've since identified other FDA-approved drugs for which that index is improved and we compounds with approximately 100-fold improvement in therapeutic index, which we've demonstrated in the EAE model are active. And we're currently evaluating them in combination with immunosuppressant drugs to identify an optimal combination, which could well be benztropine or clemastine but may be another FDA-approved drug.

MSDF

You're at very early stage in terms of clinical utility of these things in MS. But is there any way to separate out the negative antimuscarinic effects that affect people taking drugs for overactive bladder and various other things from their therapeutic effect? Or is it really intrinsic to attacking that receptor?

Dr. Lairson

That's the key point. So we do think that it's that on-target toxicity which is going to potentially limit this class of compound, which is why we're looking for these other compounds and where we have an improved therapeutic index of inducing remyelination versus antagonizing those receptor subtypes. And likely this class of drugs – and any class of drugs that induces remyelination – is going to have to be used in combination with immunosuppressant drugs. It will require a careful clinical evaluation to figure out which combination will be the most effective and what doses will be safe.

MSDF

But you also have been doing T-cell assays I take it in looking at benztropine in your work. So what goes on with immune modulation? Is there any effect there?

Dr. Lairson

So we did extensive studies with benztropine to evaluate its activity in not just T-cell biology but also macrophage biology both in vitro and in vivo. And we found benztropine had no affect on in vitro or in vivo T cell numbers or activity in terms of cytokine production. It has no affect on macrophage polarization in vitro or in vivo, including looking at spinal cords of animals. We don't think that it's acting through a peripheral immune system effect. We can't rule out an important concept that came out at a recent meeting was we need to look at the affect of these compounds on microglial cell activation in the brain and also in astrocyte activation.

MSDF

So it looks like it's a pure remyelination effect at this point and not really an immunosuppressive effect, which would argue for having to use it in conjunction with today's drugs for MS.

Dr. Lairson

Correct, that's our current reasoning, yeah.

MSDF

Have you looked at other models other than cuprizone?

Dr. Lairson

Yeah, we looked at the EAE…PLP-induced EAE model of relapsing-remitting MS, and we've looked at the MOG model of progressive MS and the cuprizone model. Yeah, those are the models we've looked at to date.

MSDF

With similar results?

Dr. Lairson

The compounds we've evaluated have all been active in in those models.

MSDF

Do you have an idea of the mechanism of action how this is actually working in the oligodendrocyte precursor cells?

Dr. Lairson

Downstream of the muscarinic receptor…so as I said, based on pharmacology, these classes of compounds – these neurotransmitter receptor modulating agents – are notoriously pleiotropic in that they had multiple receptor subtypes in the brain. So benztropine, for example, it hits nicotine and histamine receptors in this dopamine reuptake inhibitor in addition to being an antimuscarinic. We've shown that those activities are not responsible for inducing OPC differentiation. However, as I said, we've identified multiple compounds that do inhibit muscarinic receptors – specifically receptor subtypes 1 and 3 – that do not induce OPC differentiation. So we think there's a second target; we're actively trying to identify what that second target and downstream mechanism is.

MSDF

Do you think the same compound would attack both targets, or are you going to need to give multiple compounds to hit multiple targets very selectively as I would think would be the hope?

Dr. Lairson

The existing compounds we have the argument is that they are hitting both of these targets to induce the differentiation. In that, there's a number of compounds that do hit the M1/M3 receptors that do not induce differentiation, which argue that you need both. The compounds we've identified fortuitously hit both of the necessary targets.

MSDF

In the antimuscarinic field, often the goal is to be very selective and limit activity at different receptors, but it sounds like you want some overlap here.

Dr. Lairson

Exactly. We've also initiated some medicinal chemistry where we're trying to see if we can dial in potency for the second target. So we know if benztropine is active on muscarinic and low nanomolar can we improve its potency in the OPC assay by dialing in potency on that second target?

MSDF

By modifying the molecule?

Dr. Lairson

Yeah, so making analogs of existing active antimuscarinic agents and then evaluating their activity in the OPC differentiation assay, as well as evaluate their antimuscarinic activity.

MSDF

Are you hoping that the same active part of the molecule hits both receptors, or have you ever considered making a bifunctional molecule that would be best at both receptors?

Dr. Lairson

If we knew what the other receptor was, we could potentially address that, or you could argue a bifunctional versus having two unique compounds so it would be you'd have to evaluate that in vivo I think, yeah. The other argument for moving away from this is that as soon as you make a change to that compound it's no longer an approved drug, and you have to go through the rigor of bringing that to the clinic.

MSDF

Now in your screening, you're using a lot of drugs – a lot of compounds at this point – that have already passed phase 1 screening or phase 1 clinical testing, and this has shown safety. Does that speed up do you think the approval process if these things look active?

Dr. Lairson

It does. So UCSF has actually initiated a phase 2 trial to evaluate clemastine in MS. So they were able to immediately proceed from a screening result to a clinical trial because it's an approved drug.

MSDF

And just about Calibr, your institute. You have full facilities for taking this from screening up to what stage?

Dr. Lairson

Up to the rodent proof of concept stage. So we have a high throughput screening facility, as I mentioned, and then we have a medicinal chemistry group, a pharmacology group where we can do pharmacokinetics in-house and then in core biology. So we take it to the rodent proof of concept.

MSDF

Do you do any synthetic chemistry, or this is all screening of existing molecules?

Dr. Lairson

Yeah, we do significant amount of synthetic chemistry so we have a group of 20 chemists – medicinal chemists – that are making analogs. And we do a significant amount of contract research to get compounds and analogs made.

MSDF

What have we missed, or what do you think is important to add, if anything?

Dr. Lairson

The other aspect of our program is we've identified novel compounds for which their mechanism of action is unclear. So we've identified multiple scaffolds. We've focused on three of those, which have been subjected to medicinal chemistry optimization. So we identified screening hits, which we were unable to evaluate in the rodent models due to their pharmacokinetic property. But we've now identified analogs of those compounds which are potent in the OPC assay, in which we can achieve reasonable levels in the brain. So we're currently evaluating those in these preclinical rodent models. And once we demonstrate efficacy there, we'll then go and evaluate their mechanism of action.

MSDF

You test these compounds first in a phenotypic sense to see if they actually do something that you want done. And then you trace it back to mechanism of action?

Dr. Lairson

Correct. That's our general approach for a lot of assays. So rather than looking at a validated, biochemical target, typically we'll just look for small molecules that induce the cell fate decision that we're interested in. For me, personally, it's the most interesting part of the project is I’m figuring out how those compounds that we rule out known mechanisms how they're actually acting. So we do the mass spec-based proteomics to figure out the specific protein target. And then we use standard cellular molecular biology techniques to elucidate the downstream mechanism of action.

MSDF

So I suppose the phenotype you're looking for in the case of this research we've been discussing is remyelination. How do you look for that activity?

Dr. Lairson

The remyelination activity in vitro? We use a co-culture assay, which we collaborate with Rusty Gage at Salk where we pre-differentiate neurons in a dish and then co-culture with our oligodendrocyte precursors plus or minus drug and then look at the ability of those drugs to enhance the rate of myelination of co-cultured axons.

MSDF

And you just stain the cells in vitro looking for myelin production or myelin basic protein?

Dr. Lairson

Exactly, yeah. So we just look at myelin basic protein co-localization with axon.

MSDF

Very good. I appreciate it, thanks.

Dr. Lairson

Absolutely. Thanks very much for your interest.

[transition music]

MSDF

Thank you for listening to Episode Fifty-One of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is vice president of scientific operations.

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

[outro music]

[intro music]

Host – Dan Keller

Hello, and welcome to Episode Fifty of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.

This week’s podcast features Dr. David Tabby, who discusses the use of balance vests in people with MS. But first here are some new items in the MS Discovery Forum.

According to our curated list of the latest scientific articles related to MS, 65 such articles were published last week. We selected one of these articles as an Editor’s Pick. It’s a large case-control study in the European Journal of Clinical Investigation demonstrating that MS is associated with more than a six-fold increase in the risk of venous thromboembolism. To see this week’s articles, go to msdiscovery.org and click on Papers.

Our Drug-Development Pipeline includes continually updated information on 44 investigational agents for MS. During the month of July, we added 6 new trials, we updated information on 6 other trials, and we added 56 other pieces of information. The drugs with important additions and changes are alemtuzumab, dalfampridine, dimethyl fumarate, fingolimod, glatiramer acetate, GNbAC1, interferon beta-1a, interferon beta-1b, masitinib, natalizumab, rituximab, RPC1063, and teriflunomide. To find information on all 44 compounds, visit msdiscovery.org and click first on Research Resources and then on Drug-Development Pipeline.

[transition music]

And now to the interview. Dr. David Tabby is an adult general practice neurologist with a subspecialty in multiple sclerosis in Bala Cynwyd, Pennsylvania. He was formerly associated with Drexel University College of Medicine. We spoke about balance vests for people with conditions that impair their balance. He first describes what the vest is.

Interviewee – David Tabby      

The balance vest looks like a bulletproof vest; it's a black nylon vest that's worn over the torso like a typical vest. And it was discovered by accident, I suppose, by a physical therapist from California called Cindy Horn who was treating people with Parkinson's disease, and she was troubled by the fact that these people tended to be forward-flexed at the hip and walk like they're looking at the floor. So she wondered if she put some weights on their back, if she could tip them more upright. And she did that and it worked, but she also discovered that people had better balance. Falls is a major cause of morbidity and even mortality in Parkinson's disease, so this was big.

So the next step was that she developed a system to figure out how to maximize the weighting of the torso, consisting of perturbations – pushes really – of the shoulders forward or back or side to side, twisting the pelvis and seeing the rebound to that, and figuring out by trial and error a way of using weights to dampen those oscillations really. She worked on it for years; this process started about 15 years ago, I think, maybe more than that now. And then she realized that there were other people besides Parkinson's patients who could benefit from it. Multiple sclerosis patients turned out to be a big one, but other types of people with cerebellar disorders, and ataxias, and even peripheral neuropathy; if the problem was balance, it seemed like the balance vest could make a difference.

Interviewer – Dan Keller          

What about for vestibular dysfunction, maybe those 20% of people who shaking their head doesn't fix the problem?

Dr. Tabby

I don't think we have a lot of data on vestibular patients, but that's important. It's not exactly the topic of this talk, but we've had some really great results in post-concussive injury. My theory on this is that kind of everything doesn't work right after concussion, you have to think consciously about all these things that used to be automatic, including walking. And if you imagine that you only have a finite supply of mental energy to expend on different tasks, if you're expending a lot of that on balancing, there's not as much left for thinking and talking and other normal cognitive tasks. So we've seen unexpectedly some significant improvements in cognitive function from people who had concurrent balance disorders freeing up, if you will, their cognitive reserve to do what it's supposed to do instead of worry about why you're not falling over.

MSDF

Is there a proposed mechanism here; is it only dampening oscillations or is there some sort of perceptual thing that it's enhancing, or how's it working?

Dr. Tabby

This is not known, there are only theories at this point. I had started on a study while I was still at Drexel with the Department of Physical Therapy who had built a device for measuring sitting balance; you know, taking the entire lower extremity out of the equation. It's basically like a chair without legs on a half dome. So if you don't have a disorder, in fairly short order you can teach yourself how to sit on the chair and not fall over. It sits on a very sensitive pressure plate, and then you can measure how much deviation there is from the exact center point. Your feet are strapped so you can't move them around, and you're supposed to hold your arms over your chest, so you have your torso and head to move around. Then you try to do certain exercise. You're looking at a screen that has a big circle on it and you're supposed to roll your center of gravity forward maybe to 3 o'clock on a clock face, and 6 o'clock, and 9 o'clock, and go back to the center, and you can see how much progress you're making.

And we had started on an experiment to put the balance vest on people and see if they did better with the balance vest with the lower extremity, you know, taken out of the equation. We didn't collect enough data to make a conclusion about that. I think it's really fascinating, though, because if you carry your cell phone in your shirt pocket, doesn't that change the vector forces about your torso, but somehow we don't seem to fall over over that. Maybe it does change things but it's not big enough to notice. We need a lot of research into determining what the exact mechanism of action is for the vest, because there's a lot of question marks about it right now.

MSDF

So how do they fit this vest, adjust it? How long does it take?

Dr. Tabby

An experienced physical therapist can do a good fitting probably in 30 to 45 minutes, sometimes a little longer than that depending on how severe the problem is. We generally video the patient before, during, and after of some more objective confirmation of the changes. There are tests both in standing still and also walking. We would like to bring some more quantification into that process about ways to get data about walking, like a pressure plate that you walk over and times the interval between heel strikes and variability from the center line, but that's all in the future. It's been very just pragmatic right now. Patients almost always leave from their fitting session knowing that they could balance and walk much better than when they came in, and they're all anxious to get their permanent vest soon. It's accomplished with quarter pound and half pound weights, and to be honest, I don't know how to do it; I didn't get trained, so I don't know exactly all the principles involved, you know, where you put the weight, how far from the midline you put the weight. Do you put it up high on the torso, do you put it low on the torso?

MSDF

So counting the weights and the vest, how much extra weight is a patient carrying around, and does that become a burden?

Dr. Tabby

We don't use more than 2 lbs of weight, and then the vest itself is about 2 lbs. Now we're also working on a t-shirt or an undershirt, a close-fitting athletic-type shirt that we can incorporate the weights right into that. That's really nice because it can be worn under any clothing at all, and the complaint about it being hot won't be as relevant. It does not include a lumbar brace, as this standard brace does. A lot of patients like the brace, though, they think that that contributes somewhat to the sense of balance that they get.

MSDF

For an MS patient – and I realize they vary a lot in their disability – is it fairly easy to put this on once they have it?

Dr. Tabby

Some might require help. It zippers and tightens up with Velcro straps, so it takes some coordination to get it on.

MSDF

Is there any residual effect? I mean, you said they have an immediate effect, but once they take it off is there any benefit or do they always have to wear it?

Dr. Tabby

I'm so glad you asked that, because a lot of patients find that they can wear it intensively for two or three days and then not wear it for a day or two and still have carryover benefit. Exactly how that works, I'm not sure either, but that's what they say.

MSDF

You've used this with patients. How many in your practice have been trying it?

Dr. Tabby

We have over a hundred in the last five or six years.

MSDF

Is there any downside?

Dr. Tabby

You have to change your wardrobe. I'm kidding a little bit, but I do have a patient… You know, the vest comes in every shade of black that you want, so she changed her wardrobe to only include black so the vest doesn't look strange. You know, if you wear big, loose clothing, you could probably have it under something and it might not be obvious. You know, the fashion sense is an issue, the weight by the end of the day and the temperature.

MSDF

Sounds like those are all things that can be worked out sort of cosmetically; color and different fabric eventually or something.

Dr. Tabby

Yes.

MSDF

Have you done any of the research on this, or you've just been using it? I see there's actually a fair bit published about it.

Dr. Tabby

We have a trial that we're working out the kinks of now. We wanted to do a trial with other medications that might help with walking; I'm not sure it's going to be feasible to do that, but just accumulating other types of data that doesn't exist right now, like great systems for measuring body position and movement with small wearable sensors on the body, as well as pressure plates on the floor that you can walk along a pathway. We'd like to do more specific research in specific conditions. Of course, my interest is mainly in MS, but I know I've been able to help other patients with it. You know, it's important if this therapy is going to help more people, that there be as much published as possible that shows that this is a real phenomenon; it's worthy of patients' and physicians' attention.

[transition music]

Thank you for listening to Episode Fifty of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is vice president of scientific operations.

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

 [outro music]

[intro music]

Host – Dan Keller

Hello, and welcome to Episode Forty-nine of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.

This week’s podcast features Dr. Hugh Rosen of the Scripps Research Institute. But first here are some new items in the MS Discovery Forum.

If you’re an MS researcher, you may want to keep an eye on our Bulletin Board section, where we post a variety of news items that may be of interest. One of the items we posted this week is directly related to Dr. Rosen’s work. It’s a notice that a phase 3 trial of a sphingosine 1-phosphate receptor modulator called RPC1063 has started recruiting twelve hundred patients with relapsing remitting MS in the US. RPC1063 had its origins in Dr. Rosen’s lab.

We also recently added a notice of another clinical trial to the Bulletin Board. That one’s a phase 2 trial of oral laquinimod in primary progressive MS. And a third new Bulletin Board announcement is a request for information from the Patient Centered Outcomes Research Institute to identify patient registries and research groups with established cohorts of patients for potential collaborative research opportunities on comparative effectiveness research in MS treatment.

To read any of these announcements, go to msdiscovery.org and click first on Professional Resources and then on Bulletin Board. And if you have an announcement you think may be of interest to MS researchers, please send it to editor@msdiscovery.org. We won’t post purely promotional press releases, but if we judge the notice to be of general interest, we’ll be happy to post it at no charge.

In other news, it was a relatively slow week in published MS research. According to our curated list of the latest scientific articles related to MS, only 22 such articles were published last week. Typically at least 40 MS-related peer-reviewed articles are published weekly, and we’ve seen some weeks with more than a hundred. To see the weekly lists going back to March 2012, go to msdiscovery.org and click on Papers.

Our Drug-Development Pipeline includes continually updated information on 44 investigational agents for MS. This past week we added 2 new trials and 7 other pieces of information. The drugs with important additions are dalfampridine, fingolimod, masitinib, and natalizumab. To find information on all 44 compounds, visit msdiscovery.org and click first on Research Resources and then on Drug-Development Pipeline

[transition music]

Now to the interview. Dr. Hugh Rosen studies chemical and biological approaches to the molecular mechanisms regulating lymphocyte trafficking. I met with him in his office at the Scripps Research Institute in La Jolla, California.

Interviewer – Dan Keller

We're talking about mostly new compounds, S1P1 receptor compounds; the prototype now I suppose is fingolimod. What's in development and do they appear to offer advantages?

Interviewee – Hugh Rosen

So, firstly, let me disclose that I am a cofounder of a biotechnology company called Receptos that has licensed an S1PR1 agonist from the Scripps Research Institute, so I have and my institution have a significant interest in this particular field.

Sphingosine 1-phosphate receptors act in a number of ways to modulate immune tissue damages in both autoimmune diseases and in viral infections. They've proven to be particularly efficacious in multiple sclerosis. Gilenya, of course discovered by Yoshitomi in Japan and developed by Novartis, has proven to be a clinically useful compound in the treatment of relapsing-remitting multiple sclerosis. And it appears to do so, at least in part, by altering the ability of lymphocytes to recirculate, and thus lymphocytes to reach the target tissues where they, in fact, produce demyelinating damage to the white matter of the central nervous system, and then the signs and symptoms of multiple sclerosis. So clearly these are useful compounds.

Gilenya, of course, is not a selective small molecule, it is an agonist of four of the five high affinity receptors for sphingosine 1-phosphate – S1P1, 3, 4, and 5 – and some of the associated side effects may be attributable in part to activity of Gilenya on other receptors like the S1P3 receptor that are not required for modulation in the treatment of multiple sclerosis.

MSDF

I see that it's referred to as an immunomodulator, not necessarily referred to as a receptor agonist. Does it not have pure agonist effect? Does it have any effects either because of the other receptors or at that same S1P1 receptor?

Dr. Rosen

No. In fact, Gilenya when phosphorylated is a full agonist of the sphingosine 1-phosphate receptors, and the newer compounds that are much more selective are also agonists of the sphingosine 1-phosphate 1 receptor. And some of the effects on them for cyto-mediated by downmodulation of the receptor, but I don't use the term modulators or immunomodulators because of the activity on the sphingolipid receptors per se, I use the term immunomodulator because of some of the unique advantages that we've demonstrated in model systems and in man about altering the activity of the sphingosine 1 receptor, because one of the beauties of immunomodulation is to blunt the immune response that causes collateral damage to the tissues whilst leaving sufficient of the immune response intact to allow protection from opportunistic pathogens – bacteria, viruses, and yeasts.

So one of the most striking features that we found – and these have been in some experiments done as a collaboration between my laboratory and the laboratory of Professor Michael Oldstone here at Scripps – has been in the area of influenza; pandemic influenza causes significant collateral tissue damage by having an overactive immune response. What we show is that the sphingosine 1-phosphate 1 receptor blunts that immune response and blunts the amplification of cytokines and chemokines so that you protect from the collateral tissue damage, but you leave intact the ability to mount protective, sterilizing T cell and B cell immunity to the virus. So you can eradicate the virus, sterilize it, you can provide a long-term memory both on the T-lymphocyte side as well as on the antibody side; there's class switching, there's affinity maturation, there are good protective immunity that is produced, and all this while blunting the immune response.

This is the Holy Grail as we think about treating patients, because the window for patients with autoimmune diseases like multiple sclerosis is that window between effective blunting of the immune response and the prevention of deleterious opportunistic infections that can have life-threatening consequences. So one of the advantages that I suspect we will see over time is that the sphingosine 1-phosphate agonists will prove to be particularly well-tolerated and have a wide window between the ability to limit tissue damage and progression of RRMS, and the need to protect patients from intercurrent infections or subclinical infections that become expressed later.

MSDF

Do the other sphingosine 1-phosphate receptors interfere with lymphocyte trafficking also, or do they have other effects which nonselective ligands would then induce these adverse effects through them, or do they also have some effect in terms of trafficking?

Dr. Rosen

They don't have significant effects on lymphocyte trafficking the way that S1PR1 does, both from the chemical approaches and the genetic evidence. S1P1 is clearly a toggle switch for lymphocyte trafficking. S1P2 is involved in the maintenance of hearing and in the function of vascular smooth muscle, so it regulates blood pressure. S1P3 is involved in cardiac contractility and also in the control of coronary artery caliber and the control of the airways, so S1P3 agonism is not a useful thing, it's actually quite deleterious. S1P4 and 5 have really no rate-limiting functions, at least of which I am aware, so there may be some redundancy and may not play a critical role in the modulation of health and disease.

MSDF

Do you see compounds coming along which will be more selective and therefore not lead to the adverse effects so much? And if so, are these compounds chemically similar or do they have different structures to attach to the receptor, the S1P1?

Dr. Rosen

These are clearly different structures, they're structurally very distinct from Gilenya and from each other. Novartis have a backup called siponimod. Actelion had a compound but it's only being used in psoriasis called ponesimod. Receptos has a compound now known as ozanimod – formerly known as RPC1063 – that is in two phase 3 studies for relapsing-remitting multiple sclerosis, a two-year study called RADIANCE and a one-year study called SUNBEAM, both of which are enrolling twelve hundred patients each.

MSDF

And the RADIANCE trial results looked pretty good; I mean, you had 85, 90% effects at 12 to 24 weeks or even at a year in terms of relapse rate. Does this look like the next compound to emerge?

Dr. Rosen

I think it's likely that ozanimod will be the next compound to be submitted for the regulatory process here in the United States and probably in Europe as well. The pleasing thing about the phase 2 data for ozanimod was, in fact, both the strong efficacy signal and a very well-tolerated safety profile; in fact the adverse effect profile of ozanimod and placebo were, in fact, indistinguishable and overlapping in the phase 2 studies. In addition, this very well-tolerated, favorable safety profile has been replicated in a highly successful phase 2 study in ulcerative colitis called TOUCHSTONE that was released recently. So clearly this is a mechanism of immunomodulation that could well prove to be useful for relapsing-remitting multiple sclerosis, but also in a range of other autoimmune diseases where treatments are hard to come by.

MSDF

Even with Gilenya, I think there have been reports of a couple of cases of progressive multifocal leukoencephalopathy, so it gives a nice balance between immune surveillance and inhibiting T cell trafficking, but it seems like not a perfect balance. Does it look like that margin will be narrowed in the future with other compounds?

Dr. Rosen

It's possible that it will be. I think the critical point to bear in mind is that real-world experience in tens of thousands of patients with hundreds of thousands of patient-years is really ultimately what is required to define these very rare events that on occasions do occur, and preexisting treatments with other immune-modifying agents such as Tysabri, for instance, may predispose to issues being seen later with PML. And I think that we always have to say that long-term patient experience and physician comfort are ultimately the best guides to the risk-benefit ratio.

MSDF

I think you've identified something like four compounds in development, those are some that I had seen. Are there others, or these are really the ones to focus on at this point for people to keep an eye on?

Dr. Rosen

There may well be others that are further behind. There have been a number of others that have had safety signals, particularly liver enzyme elevations, and significant first-dose cardiac effects. Arena have a compound that has recently completed a phase 1 multiple-dosing study and will go on to phase 2. So, you know, there are additional compounds and there will be additional compounds. Ultimately, patients do best when the best compounds appear, and the only way one knows that is to test them in man over the long-haul and define that risk-benefits for patients. And, you know, these multiple efforts really reflect the fact that a field has advanced, and that advancing field really does improve through intelligent intervention our ability to offer patients a better set of choices and a better set of long-term outcomes, which is what we're all about.

MSDF

We're still focusing here on RRMS, none of this applies to the progressive phase. Is there anything coming along there?

Dr. Rosen

You know, there's been one trial in primary-progressive; this was the Gilenya trial which didn't meet its endpoints. It may be that the mechanisms in rapidly progressive MS are a little different and that we don't yet, I think, understand the pathogenesis of that rather different presentation. So I'm not aware of a good alternate approaches to that, but that doesn't mean that the understanding isn't there for that to happen over time, it simply means that I'm not yet aware of it.

MSDF

Finally, in secondary-progressive MS, we can understand what's going on, what led to it; if you limit relapses, that's good. But does it look like primary and secondary really may be overlapping but not the same disease?

Dr. Rosen

I think there may be balances of pathogenesis where you can intervene more easily in some than in others. Clearly the sphingosine 1-phosphate agonists work particularly well by inhibiting the movement of lymphocytes into the brain. The movement of lymphocytes from the perivascular cuff into the parenchyma, into the white matter, where the demyelination proceeds. However, in parallel in multiple sclerosis, there are also events where there is collateral damage to neurons; we see axonal severing, we see elements of neuronal loss. Certainly with the sphingosine 1-phosphate agonists, there is some evidence that there is a diminution of cortical thinning over time with treatment, and that may be a really good thing.

I think that the neurodegenerative components is one that is hard to get a handle on right now, and that I think that these differences will become more obvious with early treatments of the immunopathology of multiple sclerosis. And that may well separate the autoimmune inflammatory damage and its sequelae from neurodegenerative mechanisms that may be entrained, and I think we will learn a lot from looking at those subsets of patients over time, particularly as more, better, and earlier treatment modalities allow the avoidance of significant damage in most patients.

MSDF

Is there anything important we've missed or you'd like to add?

Dr. Rosen

You know, I think for all of us who try to work at this interface of therapeutics, we do so because disease is, in fact, personal. We all know patients, we've all seen the multigenerational impact and depredations of multiple sclerosis on friends and family. And I think this is the very strong underlying motivator that drives us as scientists and as physician scientists to really try and bear in mind that the basic mechanisms and the basic therapeutic approaches that we pursue ultimately need a safe and effective human face to change the lives of patients in a positive way.

MSDF

Very good. Thank you.

[transition music]

Thank you for listening to Episode Forty-nine of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is vice president of scientific operations.

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

 [outro music]

[intro music]

Host – Dan Keller 

Hello, and welcome to Episode Forty-eight of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.

This week’s podcast features Dr. Bruce Cree on the EPIC, CLIMB, and SUMMIT clinical trials in MS. But first here are some new items in the MS Discovery Forum.

We're very happy to report that MSDF has received three generous grants that will allow us to continue our mission: to focus attention on what is known and not yet known about MS and related conditions in a way that builds bridges among different disciplines. Genzyme has given us two grants. One will allow us to continue producing this weekly podcast for another year, and the other will allow us to develop an additional 12 monthly data visualizations. And Biogen has given us a grant for general operating support. None of these grants will interfere with our editorial freedom, and you can continue to count on MSDF to be an independent source of unbiased MS news.

A conference in Cambridge, Massachusetts several weeks ago sponsored by Orion Bionetworks outlined the progress and challenges in turning computational modeling into actionable knowledge in MS and other brain disorders. Allison Provost, who is Orion’s scientific program manager, has written a blog post describing the parts of the conference of particular interest to MS researchers. You can find her post by going to msdiscovery.org and clicking first on News and Future Directions and then on Blogs.

According to our curated list of the latest scientific articles related to MS, 50 such articles were published last week. To see the list, go to msdiscovery.org and click on Papers. We selected three of those papers as Editors’ Picks. Two of them are comprehensive review articles: one on biomarkers in MS and the other on MS immunogenetics. The third is an evidence-based consensus guideline on the use of MRI in MS diagnosis.

Our Drug-Development Pipeline includes continually updated information on 44 investigational agents for MS. This past week we added 1 new trial, we updated information on 3 other trials, and we added 13 other pieces of information.  The drugs with important additions and changes are alemtuzumab, fingolimod, glatiramer acetate, interferon beta-1a, interferon beta-1b, natalizumab, and rituximab. To find information on all 44 compounds, visit msdiscovery.org and click first on Research Resources and then on Drug-Development Pipeline.

[transition music]

Now to the interview. Dr. Bruce Cree is a neurologist at the University of California, San Francisco. MSDF Executive Editor, Bob Finn, caught up with Dr. Cree in his office at UCSF’s Mission Bay Campus shortly after a departmental seminar entitled “An EPIC CLIMB to the SUMMIT.” 

Interviewer – Bob Finn

Dr. Cree, welcome.

Interviewee – Bruce Cree

Thank you.

MSDF

Now EPIC, CLIMB, and SUMMIT are acronyms for three MS clinical studies. So first, what's EPIC, what's CLIMB, what's SUMMIT?

Dr. Cree

Great question. So the EPIC study is a long-term observational study now in its 11th year at UC San Francisco. It's a a cohort study of multiple sclerosis patients who have been followed annually for the last 11 years. And this cohort initially had about 517 participants, and now – in its 11th year – we have about 91% of those patients coming back for ongoing assessments. The assessments include annual MRI scans, as well as clinical assessments and the blood draws for biomarker studies.

The CLIMB study is a similar related study that was developed independently at the Brigham and Women’s Children's Hospital in Boston under the directorship there of Howard Weiner. And it is also a long-term followup study. And now, after about seven years, that study has some 217 patients who have been retained out of the original cohort. 

SUMMIT is the idea of bringing together long-term, well-curated observational cohorts from multiple sites. And the first iteration of SUMMIT will involve investigators from Basal, Amsterdam, UCSF, and Harvard who will merge together their long-term observational cohorts into a larger study. And the hope here is that we will obtain greater statistical power and be able to answer some of the more pressing questions about MS therapeutics, outcome measures, and utility of both conventional and nonconventional MRI in assisting with the diagnosis and management of patients.

MSDF

So in the EPIC study, I'm struck by the fact that you've been able to retain 91% of your patients after 11 years; whereas in the CLIMB study they've lost 90% of their patients in just 7 years. How do you account for that difference?

Dr. Cree

The EPIC study has had a great amount of support for long-term followup and subject retention. And we've gone to great lengths to keep our participants interested in the study and wanting to come back. And we have a terrific group of study coordinators who work day and night to maintain contact with our patients, inform them about why it's important for them to participate in the study. And we've even done outreach where we've gone to people's homes to perform evaluations in their homes where they were too ill to come in, as happens with multiple sclerosis as people develop more advanced disability. So we have very good retention as a consequence of the hard efforts made on behalf of the overall study by the coordinators and other members of the team. 

MSDF

Now you've used several measures of disease progression in the EPIC study, as have others in other studies. There's the EDSS, there's the MSFC, and there are several other measures. But let's talk about the EDSS first. That's probably the most commonly used measures, and it's also the one that people seem to love to hate. 

Dr. Cree

Yes.

MSDF

Can you tell me about the EDSS and what its advantages and disadvantages are?

Dr. Cree

Yeah, so the Expanded Disability Status Scale of Kurtzke is an ingenious scale that was really intended to describe where patients are at during the course of their lifespan. And it's a 10-point scale with half-point increment changes after the score of 1. And this scale has been adopted for use as the disability outcome measure in all MS clinical trials. The scale has a fair amount of inter-rater variability, which makes it challenging to administer. Because anytime you have a scale where there's a fair amount of variability it gets harder to interpret change. We did look at the EDSS systematically and looked at change over the first few years in the study and used that as a predictor for long-term disability transitions. We also looked at harder endpoints in the EDSS such as the time it takes for patients to go from no systems, disease onset, to the time where they require a cane to ambulate. 

You mentioned the MSFC, the Multiple Sclerosis Functional Composite. This is a set of scales that were developed for use in multiple sclerosis that included the Timed 25-Foot Walk, which is a measurement of how fast somebody can walk 25 feet. That is clinically relevant because the speed at which somebody walks correlates quite well with the distance they can walk. So the faster you can walk 25 feet the longer you can walk. The 9-Hole Peg Test is a test of upper arm coordination and function. And the Paced Auditory Serial Addition Test is a test of cognitive function that measures specifically the tension and processing speed. 

So we looked at these things, and we set up thresholds based on other clinical work that were considered to be clinically meaningful changes. So with respect to the Timed 25-Foot Walk and 9-Hole Peg Test, we were looking for a 20% worsening in function over the course of the trial. And with respect to the Paced Auditory Serial Addition Test – or PASAT – we were looking at the reliable change index for that outcome. And so these have been validated outcomes that are related to actual disability.

So we looked at all of these measures. And what we found was that when we looked at our relapsing MS patients about half of the patients experienced worsening in terms of EDSS change over 10 years. For the patients who had progressive multiple sclerosis, about 70% of them worsened. And then for these more stringent measures with respect to the MSFC components, we found lower proportions of patients with relapsing MS in secondary progressive or primary progressive disease had worsening in those outcomes, as well. So those were our endpoints for the study; they're clinical endpoints.

MSDF

One of the things I noticed in your talk was that there was a great deal of overlap between the EDSS and the overall MSFC score; whereas there wasn't much overlap between the individual components of the MSFC score. What is the significance of that?

Dr. Cree

Well the EDSS is itself a composite measure, and people tend to forget that. Especially earlier on in the scores that go from 0 to about 4, there you have 6 functional scale scores that contribute to the overall EDSS. That includes assessment of vision, brain stem function, motor function, sensory function, cerebellar function, bowel and bladder function, and cerebral function. And those separate functional scale scores are scored independently and then are summarized into an EDSS score between 0 and 4. After that, the EDSS score becomes really much more of an assessment of how far patients can walk until they have hit the major disability milestones of an EDSS of 6, which is walking with a cane, 6.5 a walker, 7 a wheelchair, or 8 bed bound. 

MSDF

So why is there a lot of overlap between EDSS and MSFC but not so much overlap between the components of MSFC?

Dr. Cree

So when you look at the MSFC, you have two measures to the MSFC that are looking at motor function: the 9-Hole Peg Test and the Timed 25-Foot Walk. They can also be measures of cerebellar function. Both of things are very well measured in the EDSS by the functional scale scores for pyramidal and cerebellar function. The PASAT is not as well measured in the EDSS, although we have a cerebral functional scale score it's not a very precise measure, and there's a weakness associated with EDSS. Whereas in the MSFC, it's a very precise measurement. 

When we look at the individual MSFC scores themselves, you can have patients who worsen in terms of walking, patients who worsen in terms of arm function, and patients who worsen in terms of cognitive function. And there is some degree of overlap in those three domains but not complete. And that just underscores how MS will affect different individuals differently. Some people have more ambulatory impairment, other people have more upper limb function impairment, and still other people have more cognitive impairment.

MSDF

You made an interesting analogy to rheumatology in the treatment MS: the question of whether you should treat to no evidence of disease activity. I wonder if you can talk about that analogy and the NEDA, or no evidence of disease activity, goal.

Dr. Cree

Sure. So in rheumatology in the 1990s, the discussion at that time had to do with how to treat rheumatoid arthritis. And this concept was advanced, which was a treat-to-target approach. The idea of using increasingly effective therapies to silence and suppress any evidence of active rheumatoid arthritis. And this strategy turned out to be extremely effective in treatment of rheumatoid arthritis. And instead of waiting for people to develop more disability, initiation of early highly effective treatments and really suppressing all joint inflammation became the current standard of therapy. And this has resulted in significant improvements in long-term disability in patients who are living with rheumatoid arthritis. 

So taking that example and extending it to the field of multiple sclerosis, the idea here is that you have evidence of active multiple sclerosis on MRI scans such as gad-enhancing lesions and new T2 lesions; and evidence of relapses, which are clinical manifestation of acute inflammation; and disability progression, which is looking at the EDSS score and saying okay well if we have a combined measure that looks all of these things, and we try to suppress disease activity perhaps we're going to wind up with better outcomes. And so, this metric of no evident disease activity is defined as no evidence of relapses, no evidence of disability progression by the EDSS, and no evidence of MRI disease activity. 

And it was originally developed in the context of clinical trials; specifically the pivotal trial of the natalizumab versus placebo study. And a certain proportion of patients in that study met this criteria of no evidence of disease activity. Subsequently, with more recent trials, other compounds have also been looked at and compared to their placebo or active comparator controls. And in each of these studies, you can see differences between treatments with respect to the proportion of patients with no evident disease activity. 

The field of MS today is considering use of no evident disease activity as a therapeutic strategy or goal so that one would escalate therapy to the point where you see no evident disease activity. And the hypothesis here is that if you are able to effectively reach no evident disease activity that that is similar to putting patients in remission or preventing further disability from occurring. So we were very interested to find out whether there was long-term prognostic value of this marker, no evident disease activity. 

And so, within the EPIC study, we looked at no evident disease activity over the first two years of the trial, and there was a proportion of our patients from this study who met those criteria: who had no change in terms of disability, no change in terms of clinical relapses, and no evidence of active multiple sclerosis by MRI scan. And we thought that that group would have a better outcome overall than the rest of the cohort. To our surprise, we found that there was no predictive value of no evident disease activity on any of the clinical markers that we looked at for 10 years. 

So these patients had exactly the same risk for disability progression as patients who had evidence of active multiple sclerosis. And this was very perplexing; we just didn't really understand why that would be the case until we really started to look at the impact of treatment and use of escalation therapy in our cohort. And I think that when you look at the influence of therapeutic intervention in multiple sclerosis the effect size of therapeutic intervention is so great that other markers of biological disease activity such as new lesions wind up being minimized by the therapeutic impact. And as a consequence, things that might have been predicted based on natural history studies – such as brain volume loss, new lesions – become less apparent as having clinical meaning over a 10-year period of time because of the dominant influence of therapeutic intervention. 

With respect to the no evidence disease activity, one of the questions that I think needs to be answered is do we really have the best markers for this? And if we are going to use a treat-to-target approach, are the things that are currently being looked at in no evident disease activity the right things to look at? And there is now interest in looking at other markers, as well, looking in incorporating, for example, brain volume into the no evident disease activity. And it will remain to be determined whether other ways of looking at no evident disease activity wind up performing better as a long-term predictor.

MSDF

So when you're confronted with an individual patient – a new patient early in their course of disease – every neurologist is confronted the question of whether you start them with an interferon and escalate as they progress, or whether you start them with a highly active therapy. How do you make that decision, and how does the evidence from EPIC inform that decision?

Dr. Cree

That's a great question, and I think this is probably one of the most provocative aspects of this long-term study. In EPIC, we used the escalation strategy where we began with so called platform therapies; drugs that are used as disease-modifying therapies that have been around for a long time, specifically the interferons and glatiramer acetate. And in the event that patients experienced relapses or had other markers of worsening such as brain volume loss, many of those patients were escalated onto what we would consider to be high-potency therapies. Drugs like natalizumab or medications that are off-label but still used in treatment of multiple sclerosis like rituximab or cyclophosphamide. 

So we used this escalation strategy in this cohort. And what we found was the following. Treatment escalation was not associated with improved outcomes. In fact, treatment escalation was associated with worse outcomes in some patients. Now, why would that be the case? Well there's probably a confounder there of the indication to treat so that the patients who were getting escalation therapy are doing worse, and so they get the escalation therapy. So what we don't know from this study is if those patient hadn't gotten escalation therapy how would they have fared? We can't answer that question. That would require a randomized controlled trial. 

But what this study does provide is this provocative idea that perhaps escalation therapy was really too little too late. That we were identifying a group of people who were at high risk of disability progression, but we weren't really setting things back to restore them onto a normal pathway and certainly not to prevent long-term disability. And this raises the idea that perhaps we should be utilizing these higher-potency therapies earlier. Now, that type of approach – the maximal efficacy approach – doesn't have data yet to support its use, but there are a few provocative studies that suggest that high-potency therapy might be associated with better outcomes. And we have the recent results of the cladribine study in clinically isolated syndrome where we had the best data yet for use of a broad-spectrum immune suppressant in terms of venting, time to the next clinical or radiographic event in patients who have presented with a first demyelinating event. And that study out performed all prior trials in clinically isolated syndrome so raises the question should be using an aggressive therapy right from the get-go?

And then, we have the alemtuzumab pivotal trial where alemtuzumab was compared head-to-head versus interferon beta-1a twice weekly in newly diagnosed patients. And in that study, alemtuzumab also out performed interferon beta-1a on many of the short-term markers of inflammatory disease activity. And we recently saw long-term data with alemtuzumab indicating that those patient do really quite well over a four-year period of time. So actually midterm data. 

So we have a few lines of evidence to suggest that perhaps we should be using these high-potency therapies earlier. What we don't know is the relative risk-to-benefit profile. Certainly these higher-potency therapies carry greater risk to the individual subjects who are treated with these medications. And what we ultimately have to determine is whether those risks at a population level are worth the potential benefits of using a greater potency therapy early on in the course of MS. 

It's my opinion that it's unlikely that the pharmaceutical industry is going to answer this question for us definitively. This type of approach to compare escalation therapy to high-potency therapy or maximal efficacy therapy from the get-go will require quite a bit of time of followup – at least five years if not longer – and will require large studies. So it seems to me unlikely to be endorsed by the pharmaceutical industry. It also seems unlikely that it's going to be sponsored by national organizations such as the National Institute for Neurological Disease and Stroke because of the extremely high costs associated with this type of clinical trial. 

So that raises the question how are we going to answer this pressing unmet and unanswered question? And I think observational studies such as EPIC will be able to do this when merged together with other long-term followup cohorts. Today we have treatments that we didn't have 10 years ago, for example, fingolimod, dimethyl fumarate, alemtuzumab. These medications are currently being used in clinical practice. And I think we should be responsible for aggregating data on the patient experience with these medications, putting it into a systematized process for analysis, and aggregating this type of data across multiple centers. And that really is the goal of SUMMIT, which is going to involve pooling together our patient experience with our existing cohort, as well as new cohorts from UCSF, from Harvard, from Basal, from Amsterdam, and hopefully from many other MS centers as well. And then, with that pooled data, we'll hopefully be able to answer this question in a meaningful way. 

MSDF

Well, Dr. Cree, thank you very much. 

Dr. Cree

My pleasure. 

[transition music]

MSDF

Thank you for listening to Episode Forty-eight of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is vice president of scientific operations. 

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

[outro music]

[intro music]

Host – Dan Keller

Hello, and welcome to Episode Forty-Seven of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.

This week’s podcast features the second part of a two-part interview with Dr. Hans Lassmann, who discusses oxidative stress as a mechanism of tissue injury in progressive MS. But first, here are some of the new items in the MS Discovery Forum.

According to our curated list of the latest scientific articles related to MS, 56 such articles were published last week. To see the list, go to msdiscovery.org and click on Papers. We selected two of those papers as Editors’ Picks. One of them includes revised guidelines from the Association of British Neurologists on prescribing disease-modifying treatments for MS. The other describes an international consensus on diagnostic criteria for neuromyelitis optica and related disorders.

Our Drug-Development Pipeline includes continually updated information on 44 investigational agents for MS. During the month of June, we added 10 new trials, we updated information on 6 other trials, and we’ve added 67 other pieces of information. The drugs with important additions and changes are alemtuzumab, cladribine, cyclophosphamide, daclizumab, dalfampridine, dimethyl fumarate, fingolimod, glatiramer acetate, idebenone, interferon beta-1a, interferon beta-1b, laquinimod, rituximab, natalizumab, and ocrelizumab. To find information on all 44 compounds, visit msdiscovery.org and click first on Research Resources and then on Drug-Development Pipeline.

[transition music]

Now to our interview with Dr. Hans Lassmann of the Medical University of Vienna in Austria. Last week we spoke about biomarkers, and this week we’ll discuss oxidative stress as a mechanism of tissue injury in progressive MS.

Interviewer – Dan Keller

What's interesting there at this point?

Interviewee – Hans Lassmann

The big problem in multiple sclerosis is that we have very good therapies for the early stage of multiple sclerosis, and they all interfere with the inflammation and the immune system. But when the patients have reached a progressive stage of the disease, then all these therapies are currently noneffective. So the key points were to define what are actually the mechanisms of inflammation and tissue injury in the progressive stage of multiple sclerosis, and there are still a lot of open questions. It is clear that even in the progressive stage there is an inflammatory process, and this inflammatory process is associated with active tissue damage. From that certainly we cannot definitely conclude that the inflammatory process drives the tissue damage; however, it's clearly associated.

Now, we were then very interested to see what are the mechanisms of tissue injury. And this involves, first of all, studies on the nature of the inflammatory process. And here what we found is that in the progressive stage of multiple sclerosis the inflammatory reaction is predominantly hidden within the central nervous system behind a repaired blood-brain barrier. So that means this inflammatory process is no longer really under control of the peripheral immune system. And also, the therapies which we have currently mainly interfere with immune functions in the periphery, and they have actually very little access to an inflammatory process which is taking place within the central nervous system.

So that means that new drugs have to be developed and tested which actually exert an antiinflammatory or some neuroprotective action directly within the central nervous system. And there are now a number of the large companies fully engaged in this process, and there are new candidates coming up, which will have to be tested in proper clinical trials in patients with progressive MS.

The second question, which we have mainly addressed during the last year, was the mechanisms how the tissue damage is induced. And in this regard, we concentrated on cortical lesions in multiple sclerosis, which are very, very specific for the disease. And we compared in gene expression studies these cortical lesions not only with normal controls but also with inflammatory controls. And we used here a disease which has very similar inflammatory infiltrates, as you see in multiple sclerosis brain, but doesn't lead to the MS typical demyelination, and this is tuberculous meningitis. And then we also used as a control for neurodegeneration Alzheimer's disease just to see what is a reaction in gene expression due to degeneration of neurons.

And when we did that, actually it was interesting to see that there were relatively few genes which were specifically changed in their expression in multiple sclerosis patients in comparison to these other disease controls. And these genes were, in part, associated with inflammatory processes. A large part of the genes were associated with a more or less single pathway of tissue injury, which includes oxidative injury leading to mitochondrial injury and its secondary consequences. And then, there were also some genes involved which were MS specifically related to tissue regenerative processes.

We have then looked in further detail, and it now turns out that this cascade of oxidative injury leading to mitochondrial dysfunction and with that to a state of energy deficiency is actually one of the major driving forces of neurodegeneration in the progressive stage of multiple sclerosis. So this oxidative injury is, in part, driven by the inflammatory process. But it is also augmented by factors which are related to age of the patients and to the accumulation of lesion burden due to the chronic disease.

So here the central portion is the activation of microglial cells which can, on the one hand, be activated in the inflammatory process, but they also get activated when tissue is damaged due to completely different causes. And they also get activated just simply in an aging process. And in this respect, then they get activated in a pro-oxidative form. And then, the tissue injury can further be propagated through additional age-related changes, including, for instance, the accumulation of iron in the central nervous system and also obviously the chronic microglia activation due to retrograded and anterograde degeneration when lesions already present within the central nervous system.

MSDF

Are the microglia just overdoing what they normally would be expected to do? I mean macrophages use oxidative systems to get rid of pathogens.

Dr. Lassmann

Yeah, this is absolutely true. That is a key element of microphage and microglia function. And this is exaggerated in both the aging process, as well as in the chronic inflammatory state like multiple sclerosis. The question only remains what is really driving this massive microglia activation in MS, which is even more and more pronounced than even in very severe other inflammatory diseases of the central nervous system.

MSDF

Can you identify or has anyone identified factors that disappear with aging or are increased with aging that may lead to this state?

Dr. Lassmann

That is also not really very clear now. I think one interesting aspect is that this massive microglia activation in the direction of oxidative stress you don't really see in rodents and even not in primate experimental models; you see it in humans. And the reason for that is not completely clear, but it may very well be that environmental factors actually play a major role. I think one of the major differences between humans and these experimental animals is that the experimental animals are genetically very homogenous; they are generally inbred strains. And the second is that they are kept under a very constant pathogen-free environment. And this is very different in a human situation, and these animals also have a very … standardized diet. Now this is completely different in human situations, and there are certainly many factors, including peripheral infections but also including diet changes, and many other factors can actually have an influence on microglia in the central nervous system.

MSDF

And experimental animals also have optimized diets; people have figured out the nutrients they need I suppose. They're getting a good diet compared to people who knows how everybody is eating these days.

Dr. Lassmann

Yes, that's absolutely the case. They have a standardized diet, and they certainly are not exposed to very much of the fats, for instance, which we take into when we eat fat pork meat.

MSDF

Do any of the antiinflammatory agents modify the course? Things like lipoxygenase inhibitors and things like that? Not necessarily NSAIDs but now that you bring up fats?

Dr. Lassmann

I think there is certainly an aspect behind that is that lifestyle control certainly has a beneficial effect. One can just see that in a way that environmental lifestyle factors, which actually also increase the risk for vascular injury or other things, will be certainly deleterious in a patient with progressive multiple sclerosis where the brain is already damaged due to the original disease process and where the functional reserve capacity of the brain is already partially exhausted. So in that case, even minor changes – which are related to lifestyle or aging – will have a more dramatic effect in such a brain than in a normal aging brain.

MSDF

Finally, circling back to something you said at the beginning, in progressive MS I think you said that the immune system the cells have now entered the brain, but the blood-brain barrier has – once again – become a real barrier. So do you really have an immune response running autonomously in the brain no longer subject to any sort of peripheral control?

Dr. Lassmann

Yeah, this is certainly a very important open question. We know that the inflammatory cells are present within the central nervous system in the progressive stage and that they are associated with the degenerative processes and the demyelination. We know currently very little about the exact phenotype and functional activation of the inflammatory cells within the central nervous system. This is actually a large research project, which is running currently in my lab, to try to define exactly the functional polarization of the cells within the MS lesions and to determine their activation state, their proliferation rate, and so on.

What we can say from our preliminary data on that is that they are present, they are in part activated. They also express certain transcription factors, which would be associated with a proinflammatory state in the central nervous system. However, overall all these changes are relatively small in comparison to an acute, for instance, virus-induced inflammatory process in the brain. So it seems to be that there is a slow and low-grade activation state which, however, could be completely sufficient to drive the degenerative process in the patients. But that is not the final answer yet.

[transition music]

MSDF

Thank you for listening to Episode Forty-seven of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is vice president of scientific operations.

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

[outro music]

Hello, and welcome to Episode Forty-Six of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.

This week’s podcast features the first part of a two-part interview with Dr. Hans Lassmann, who discusses biomarkers in multiple sclerosis. But first, here are some of the new items in the MS Discovery Forum.

According to our curated list of the latest scientific articles related to MS, 61 such articles were published last week. To see the list, go to msdiscovery.org and click on Papers. We selected two of those papers as Editors’ Picks. One, on the prevalence of pain in MS, found that around two-thirds of MS patients experience pain, and this symptom is associated with disability, depression, and especially anxiety. The other editor’s pick is a study of a toxin produced by Clostridium perfringens, a common bacterium often found in the gut that produces an MS-like disease in sheep. This epsilon toxin selectively kills oligodendrocytes while preserving all other neural elements.

Our Drug-Development Pipeline includes continually updated information on 44 investigational agents for MS. During the past week we added 2 new trials and 5 other pieces of information. The drugs with important additions are dalfampridine, dimethyl fumarate, and fingolimod. To find information on all 44 compounds, visit msdiscovery.org and click first on Research Resources and then on Drug-Development Pipeline

[transition music]

Now to the interview. Dr. Hans Lassmann of the Medical University of Vienna in Austria, is one of the most prolific and highly respected MS researchers in the world. In this first part of a two part interview, Dr. Lassmann discusses biomarkers in MS and related conditions such as neuromyelitis optica and how the two conditions may differ important for therapy.

Interviewer – Dan Keller

Let’s talk about new markers in MS or differentiating conditions from MS. What’s coming along, and what do we know now?

Interviewee – Hans Lassmann

Well, there has been a very important development during the last years. And this was the technical development of assays which can really identify pathogenic autoantibodies which can modify the inflammatory process in the central nervous system. The major trick behind was that these assays are, in essence, based on cells which are transfected with the respective antigen, and so they express the respective antigen on the surface of the cell. And one can now identify those autoantibodies which really bind to the surface of the cell and are pathogenic, in comparison to those antibodies which recognize epitopes, for instance, within the cells, which cannot be reached by the antibodies in the in vivo situation, and which, therefore, are not pathogenic.

MSDF

Can you give me some examples of these kinds of antibodies?

Dr. Lassmann

So the first antibody which was the antibody against aquaporin 4, which has been shown to be associated with neuromyelitis optica, at least with a large fraction of patients with neuromyelitis optica. And this antibody then was very well characterized, and it turned out that it is directed against aquaporin 4, which is a water channel in astrocytes. And when patients have these antibodies on the background of an inflammatory disease in the central nervous system, these antibodies can reach their astrocytic targets and destroy the astrocytes, which then leads to secondary demyelination and neurodegeneration.

Having these antibodies, it was then possible to define the clinical spectrum of the disease, and it turned out that it is very strictly associated with neuromyelitis optica, but that the spectrum of the disease is broader than only affecting the spinal cord and the optic nerve. So these patients actually have also lesions in other regions of the brain. But they are still different from those lesions which you see multiple sclerosis.

It was then also possible to define the clinical spectrum of the disease. And, again, differences to multiple sclerosis became very clear. And, finally, it was also possible to then look in these patients with these aquaporin 4 antibodies how they respond to the current treatment strategies which have been established for multiple sclerosis. And it turned out that several of the key therapies for multiple sclerosis, including interferons but also natalizumab or fingolimod, can actually make the disease worse in patients with neuromyelitis optica.

So that was the first example that a disease which has originally been defined as a disease in the spectrum of multiple sclerosis has emerged as a separate and distinguishable disease which requires also different treatment in the patients.

MSDF

It seems like neuromyelitis optica has components of autoimmune disease. So why do these compounds that work in MS potentially make the condition worse in NMO?

Dr. Lassmann

This is currently not yet clear. One possibility is that the action of pathogenic antibodies makes the difference. The immune mechanisms are certainly different in a purely T-cell mediated disease, in comparison to disease which is mediated by a combination of T-cells and antibodies. And that could possibly explain why differences are seen.

There is another possibility is that some of these drugs actually stimulate the B-cell response or increase the B-cell response in the peripheral blood, and with that possibly also the antibody response. So, in that case, the T-cell mediated inflammation would be suppressed, but the antibody-mediated effects would be enhanced. And that could certainly also play a role. But these are, at the present moment, not proven.

MSDF

But even in MS there’s evidence for B-cell trafficking and B-cell participation, but it seems to be less important or am I off base?

Dr. Lassmann

No, this is a very interesting question. There is clearly a B-cell component in multiple sclerosis, and it has also been shown that depleting B-cells, for instance, with an antibody against CD20 can actually have a very good therapeutic effect in multiple sclerosis. However, we have to keep in mind that B-cells not only produce antibodies, but they have also other immunological functions. So one function, for instance, is that they help the T-cells, for instance, by very efficient antigen presentation. So by eliminating B-cells, you get also a decrease of the T-cell response. But this is not only one possibility. There are other possibilities that B-lymphocytes actually can also produce cytokines – proinflammatory cytokines – which may directly act on the tissue and damage the tissue independent from antibodies.

MSDF

Getting back to NMO, if someone tests negative for antibody, but has clinical signs, does that rule out NMO or are you just not detecting antibodies or is it always required or not?

Dr. Lassmann

So it rules out an aquaporin 4 antibody associated form of NMO, but a fraction of NMO patients – it’s around between 10 and 20% – which have a clinical presentation of NMO, but have no antibodies against aquaporin 4. There is currently very much effort to define what is the mechanism in these patients. And it turned out that a fraction of these aquaporin 4 antibody-negative NMO patients actually have antibodies against myelin oligodendrocyte glycoprotein.

And this leads, actually now, to a second type of disease which can be separated from multiple sclerosis. These are patients with high titers of pathogenic antibodies against myelin oligodendrocyte glycoprotein. Now, again, these patients, when you look at them at pathology, you would clearly define the disease as multiple sclerosis because they have inflammation, and they have very selective primary demyelination. And this is different from what you see in NMO where the astrocyte pathology is the earliest event. But in those patients with the MOG antibodies, its demyelination sort of hallmark, actually, of multiple sclerosis…of the disease process in multiple sclerosis.

However, when you now analyze these patients with mock antibodies, clinically you see that the clinical presentation is different from the classical presentation of multiple sclerosis patients. These antibodies are, for instance, frequent in children with inflammatory demyelinating disease of a spectrum of acute disseminated encephalomyelitis or relapsing disseminated encephalomyelitis or even patients with a disease similar to relapsing, remitting multiple sclerosis. This is in children.

In adults, you find these antibodies in a fraction of NMO patients. But there are also other patients who have a disease which is more similar to what is seen in multiple sclerosis, with the exception that they have relatively large and aggressive lesions, and also that they have, relatively frequently, lesions in the brain stem such as, for instance, the pons or the medulla oblongata. And, again, it seems to be that here a new disease entity appears which can be separated from multiple sclerosis.

Regarding therapy of these patients, we don’t have yet the data which we need to have. It can be speculated that the therapeutic response may possibly be more similar to those patients with NMO in comparison to the classical MS patients, but to know that we would have to have much larger cohorts of patients who have been treated with the different regimes.

MSDF

Do some of these do worse on the typical MS treatments such as natalizumab or fingolimod?

Dr. Lassmann

These data currently are not yet existing. It’s also because, due to these possible problems related to NMO, generally now, patients with mock-antibody-associated diseases are more likely to be treated with global immunosuppression or with rituximab, so the anti-CD20 antibody. And clinicians are very reluctant to use these therapies which have been shown to make disease worse in NMO in these mock patients. So we don’t have the data, currently.

MSDF

Are there separate etiologies, does it look like here, the MOG versus classical MS?

Dr. Lassmann

This comes to the important question about the etiology of MS in general. We have to admit that we don’t know what is the real etiology of multiple sclerosis. It is thought to be an autoimmune disease, but this is not finally proven. It may also be associated with infections – Epstein-Barr virus infection is, for instance, one possible example. And there are certainly other theories also, which discuss completely different mechanisms of disease pathogenesis in multiple sclerosis. It is clearly that all these diseases, including NMO, mock antibody associated disease, and MS are chronic inflammatory diseases. But what drives the inflammation is currently not yet known.

MSDF

Is it possible there’s an initial insult to oligodendrocytes which then sort of precipitate a chain reaction cascade?

Dr. Lassmann

This is also one of the theories which is put forward, but one has to say that with a bit caution, because there are experimental models where you can actually destroy oligodendrocytes in the central nervous system which do not lead to an autoimmune disease which is somehow related or similar to multiple sclerosis.

MSDF

Anything interesting or important to add on the subject, in this context?

Dr. Lassmann

I think what is now of interesting new research line is to search for additional autoantibodies in the population of multiple sclerosis patients. There are indications from pathology that there are certainly more patients who may have pathogenic autoantibodies, in comparison to those patients which now can be identified as NMO or mock-autoantibody-associated disease. There is a relatively recent study suggesting that another channel, a potassium channel on oligodendrocytes and astrocytes, the KIR4.1 channel, may also be a target for pathogenic autoantibodies in multiple sclerosis. Here, however, we are still in the very early stage because the test systems are not yet fully reproducible. And we will see in the future whether this antibody association with the KIR4.1 antibody really holds true in MS patients. And if that’s the case, what patients are they and whether they differ in any way in their clinical presentation or also response to therapy.

MSDF

Is there a way to survey patients and essentially see what commonalities they have in antibody reactivity, and zero in on it that way, looking at a wide array of antibodies in various patients and seeing if they have reactivities in common?

Dr. Lassmann

I think this is valid as a second step. But there is another alternative strategy which is now very well established also for other diseases, including paraneoplastic diseases or other autoimmune diseases. In that case, one can actually take the sera of the patients, and there are now new technologies developed where you can put these sera, for instance, on brain sections – normal brain sections – of either humans or animals and test whether they bind to specific structures.

This has been tried for nearly 30 years now, but only recently, new technologies became available which make that in a much more specific way. And this has been very successful in identifying new diseases which are associated with antibodies against a variety of neurotransmitter receptors or ion channels. So they certainly, in general, have not the spectrum of multiple sclerosis. They may have epilepsy. They may have psychosis. They may have motor neuron diseases, other things. But, on the other hand, the same technique can also be used to identify in multiple sclerosis patients whether some of them have actually antibodies which bind to brain tissue. And when that is established, one can actually then isolate the specific protein with the antibodies out of the brain tissue, and then, with modern molecular biology technology, can identify the antigen.

This is a strategy which has very nicely and very successfully shown for other diseases. And this was also, in principle, the strategy how people found evidence for these, for instance, KIR4.1 antibodies and also for the NMO antibodies.

MSDF

Finally, do you envision being able to develop specific treatments if you find out specific autoantibodies or causes of some of these conditions?

Dr. Lassmann

It may very well be. I think there are two dimensions on that. The one dimension is that such patients have pathogenic autoantibodies, and that certainly will have implications for therapy. That means that you will try to block the pathogenic action of the antibodies in general. In that case, it doesn’t make a difference whether the antibody is now directed against a neuron or against an astrocyte or against an oligodendrocyte. And this is a strategy which is actually now already approached in many different conditions, and neuromyelitis optica certainly is a disease where this is relatively advanced in this respect.

Now, the other possibility would be to try to find therapies which are then counteracting specifically the destruction of the particular cells which contain the antigen. So it can very well be that, for instance, an antibody against a neurotransmitter receptor will have a different implication on neuronal function, in comparison to an antibody against an astrocyte or an oligodendrocyte. Here, if these are just blocking antibodies and not antibodies which destroy the tissue, one can actually then try also symptomatic therapies with interfering with these channels directly.

MSDF

Is there any thought towards trying to induce tolerance or clonal deletion of the pathogenic clones?

Dr. Lassmann

This is obviously the dream of immunologists, and it would be extremely attractive. And it works extremely well in inbred mouse models with a very well-defined disease induction process. The strategy is very dangerous in a genetically heterogeneous population and also in a disease process which may be induced by different mechanisms. So, in that case, the big danger is that this tolerizing strategy in certain patients, for instance, with a certain histocompatibility genetics, actually is counterproductive and increases the immune response. And this is actually a problem which is very, very difficult to solve, in the aim of translating this mouse data into humans.

[transition music]

Thank you for listening to Episode Forty-six of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is vice president of scientific operations.

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

[outro music]

[intro music]

Host – Dan Keller

Hello, and welcome to Episode Forty-Five of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.

This week’s podcast features an interview with Dr. Simon Hametner, who discusses the role of iron in multiple sclerosis. But first, here are some of the new items on the MS Discovery Forum.

According to our curated list of the latest scientific articles related to MS, 59 such articles were published last week. To see the list, go to msdiscovery.org and click on Papers. We selected two of those papers as Editors’ Picks. One, published in Nature Reviews Neurologyproposes a definition of aggressive multiple sclerosis as well as a treatment algorithm. The other editor’s pick, published in the journal Neurology, reports on a randomized, placebo-controlled study on patients switching from natalizumab to fingolimod, concluding that shorter washout periods may be better.

Our Drug-Development Pipeline includes continually updated information on 44 investigational agents for MS. During the past week we added 3 new trials, we updated information on 2 other trials, and we added 9 other pieces of information. The drugs with important additions and changes are daclizumab, dimethyl fumarate, fingolimod, interferon beta-1a, laquinimod, and natalizumab. To find information on all 44 compounds, visit msdiscovery.org and click first on Research Resources and then on Drug-Development Pipeline

[transition music]

Now to the interview. Dr. Simon Hametner works with Hans Lassmann at the Medical University of Vienna in Austria. We spoke about iron accumulation in MS in cells of the central nervous system and what iron may be doing.

Interviewer – Dan Keller

Let's talk about iron and neurodegeneration. What specifically are you looking at?

Interviewee – Simon Hametner

We are looking at the formalin-fixed, paraffin-embedded brain tissue from multiple sclerosis patients and controls, and we're looking, for example, at iron in these tissues. We're also looking now at proteins which are engaged in the management of iron in these tissues, for example, now.

MSDF

What are you finding different in MS patients that you don't see in healthy people?

Dr. Hametner

So we see iron accumulation, for example, in microglia and macrophages in MS, which are related to MS lesions. There are, for example, some MS lesions which have macrophages around those lesions, and we don't see much of iron in macrophages and microglia in healthy control tissue. We also see iron loss in multiple sclerosis because the iron is normally stored in oligodendrocytes in the controls. And this is also the case for MS, but in MS we also see a loss of this iron in the oligodendrocytes, especially at the oligodendrocytes which are closed to MS lesions.

MSDF

Do you know the mechanism of why you're seeing these differences in iron?

Dr. Hametner

We are now performing the research to find about these mechanisms. We have some prior indications, for example, hephaestin upregulation on oligodendrocytes in the vicinity of the lesions, but these data were not so straightforward. We are now also looking for ferroportin; ferroportin is an iron exporter of glial cells, it's actually ubiquitously expressed in mammalian cells. And all the glial cells also can express ferroportin, and we found it also in the oligodendrocytes; we now undertake this research. We think that oligodendrocytes really upregulate ferroportin and hephaestin in order to export iron.

MSDF

Is the iron detrimental?

Dr. Hametner

It depends. We don't think that it is, per se, detrimental; we see loads of iron in the deep grey matter nuclei and it seems that the brain can handle that quite well. But if there is even a minor amount of iron in the extracellular space even in the ferrous form – because iron normally is stored in the ferric and the trivalent form in ferritin – but if we see even minor amounts in the ferrous form, then it might be detrimental at very low amounts actually.

MSDF

Is this a result or a marker of what's going on, or does it really contribute somehow to the disease?

Dr. Hametner

This is a very interesting question. We think that iron really colocalizes or is found and accumulated at sites where things are going on with these lesions which accumulate iron in the microglia and macrophages around them. On the other hand, you can detect it very nicely with magnetic resonance imaging today. So we think that on the one hand it does play a role in the disease pathogenesis, and on the other hand we think that we can detect really these sites of iron accumulation, for example, around MS lesions.

MSDF

Are you doing this only on fixed patient tissue, or do you have animal models of this; how are you exploring it?

Dr. Hametner

We have this fixed material on the MS, and I think it's really important to also characterize the human material in very detail to perform all the necessary analysis to characterize what's going on in the human tissue. But, of course, as you mentioned animal models, it's very important to look at the EAE models. And collaboration partners have done that from McGill University in Montreal, Juan Zarruk and Sam David, and we are collaborating with them. And actually now they have been looking at some iron transporters and we are looking at exactly the same iron transporters now in the MS tissue. And they have found it in the same cell types, these iron transporters, in the EAE model being upregulated in the course of EAE as we see now in the MS tissues actually. So we really look for confirmation also from animal models from our collaboration partners.

MSDF

And does this work with various kinds of animal models, or is it restricted to the EAE?

Dr. Hametner

This survey has now been performed on the EAE, so it is a mock EAE actually and that they have performed a relapsing-remitting mock EAE in the chronic EAE model, and they have characterized those proteins, but they also do spinal cord injury models and they have performed a very interesting experiment on iron-loading in macrophages in the course of spinal cord injury where the iron gets into the macrophages possibly from a hemoglobin source from erythrocytes in the traumatic lesional tissue. And we think that regardless of the source of iron, it has these detrimental effects in the macrophages and triggers them to have a pre-inflammatory – or so to speak, M1 state – and are detrimental to the surrounding tissue.

MSDF

This is macrophages or also microglia?

Dr. Hametner

So in the spinal cord injury model, it was mainly macrophages. In the acute phases of the EAE at the peak of the disease, it was also mainly macrophages, but later they also found iron in the animal model within microglia, as we do also in MS. We have these early lesions where there are a bunch of macrophages in these classical active lesions, and these are mainly macrophages, and if they are iron-loaded, it is in the macrophages. But for the later lesions for these chronic active lesions which have this iron ring around the lesion, we find it also within macrophages but also microglia.

MSDF

So does this change the oxidative environment inside the macrophage?

Dr. Hametner

That's a good question. We think that it does change something with the macrophages because they seem to die. So we have these dying macrophages in the EAE model, as they have observed it, but in the MS we saw this dystrophic microglia at the lesion edge. So these are microglia which are highly iron-loaded probably for some time, and they have these nice processes. And if these processes get those beads and the process fragmentation and these process budding and blips in the processes, we call them senescent or that dystrophic microglia. And we have indications that this is really related to the iron load of this microglia. And then they get diminished towards the inactive centers of the lesion. So we think that at the edge of chronic active or slowly expanding MS lesions, these get iron-loaded in microglia and they don't handle it quite well, and then they die and get diminished towards the inactive centers.

MSDF

So when they die, do they release this and is it affecting other cells?

Dr. Hametner

We believe so. We think more or less that it is necessarily released into the extracellular space if an iron-loaded cells just dies by necrosis, or apoptosis, or something in between. So it is just released into the extracellular space. It has to be taken up by other cells; for example, other microglia, or other macrophages, or even astrocytes; it seems that it is really liberated. But, of course, it is hard to say whether iron within a specific microglia has been acquired by some other microglia which has died, or by some oligodendrocyte which has died, or even another source. But the fact is although we are sure that they have really accumulated lots of iron, and given actually the concentration of iron in these microglia and the surrounding tissue, we do think that there must be other sources than only oligodendrocytes by which iron gets into these microglia.

MSDF

Where do you go from here? What do you see the steps in the research?

Dr. Hametner

 I think it is necessary to characterize these rings around lesions which have these iron-loaded microglia and macrophages, to characterize at which disease phases these rings occur, and, of course, this is very interesting because you can use itin vivo. Because one of the things we are really sure is that we can image iron within microglia at the lesion edge of those lesions very nicely at 7 Tesla of magnetic resonance imaging; we are very sure that this is iron then within microglia and macrophages. And if we can relate pathologically the disease mechanisms or the degenerative actions going on in these lesions to the presence of iron, we then can also relate our in vivo findings from MRI with the things which are going on there, like neural degeneration and demyelination, for example.

MSDF

Do you find that the iron-sensitive MRI imaging correlates with duration of the disease or stage or clinical condition?

Dr. Hametner

Yes, we think so from our pathological material. So we think that in the progressive stage of MS, there are these lesions which are the slowly-expanding lesions, and they have these chronic activity, chronic demyelinating activity at the lesion edge. And we think it's a typical feature of progressive MS. It remains to be determined whether this also holds truein vivo. If you make an MRI, an iron-sensitive MRI, and you look for iron rings around MS lesions, for example, by susceptibility-weighted imaging or by quantitative susceptibility mapping or even Ultrastar imaging, if you look at these iron rings around lesions, it remains to be determined at which disease phase is, because in the pathological material we have more of the chronic cases and we have very few relapsing-remitting. So we cannot say what's really going on in the relapsing-remitting disease because we don't have this material pathologically.

MSDF

Right, you would have to find people in various stages who probably died from something else; they're not going to be advanced MS patients at that point. Is there some relationship of your findings to the idea of oxidative stress?

Dr. Hametner

Yes, we have these overactivity for malondialdehyde or E06, which is this antibody against oxidized phospholipids, and we have found actually by working performed partly in this lab that there is a higher activity for oxidative stress of various glial cells in the lesions. But as for the microglial degeneration, we did not see so many microglia being positive for these markers. So the microglia, they seem to die, but we only have these morphological features of dystrophic or senescent microglia actually from the pathological side. On adjacent side, if you stain for iron and you stain for oxidized phospholipids, you see partly that there is a 1:1 colocalization. But we don’t see these always actually.

I think what's really clear is that there is lots of oxidative stress in MS lesions, but even in early MS lesions which on iron stainings don't have so much iron, because on these early lesions we actually see predominant iron loss. If you have a very highly active MS lesion in the early stages, you see iron loss, and you will see also oxidative damage there. So there is also other factors leading to oxidative stress, like NADPH oxidase, for example, the p22phox, the functional subunit of NADPH oxidase, which we have shown in this lab that it is upregulated on macrophages and microglia, but also in the absence of iron.

MSDF

What tips the balance between loss and iron accumulation?

Dr. Hametner

That's an interesting question, actually a complicated one. You're right, we see on the one hand iron loss, and we see iron accumulation. So in the early stages, we see iron loss around MS lesions, in the MS lesions, because oligodendrocytes try to get rid of their intracellular iron possibly to prevent the iron efflux or iron liberation, which is uncontrolled if there is demyelination and oligodendrocyte degeneration actually. So we think that inflammation in the early phases of the disease leads to this efflux, which we think also involves not only oligodendrocytes, but also astrocytes. So we now think actually that oligodendrocytes probably efflux the iron towards astrocytes, and those astrocytes then might efflux it towards the periphery even. So I think inflammation is an obvious candidate to trigger this upregulation of iron efflux mechanisms.

I think what drives the iron accumulation within the microglia at the lesion edges is a different story. We think that these are two unrelated processes. On the one hand you have these iron loss mechanisms, the iron efflux mechanisms from the oligos leading to iron loss in early MS lesions, and this seems to be a protective phenomenon; this is, so to speak, a protective reaction of the glial cells against oxidative stress. But in later lesions, in chronic active lesions with this iron accumulation within microglia and macrophages, and we don't think that they are really correlated. So we think these are two distinct processes going on in MS, probably even in two distinct phases of the disease.

MSDF

Is there anything interesting to add?

Dr. Hametner

I think the really crucial question is now to find out about the source of iron for microglia and macrophages, and even to find out about the source of iron for the oligodendrocytes. We are not so sure whether this is really transferrin-bound iron entering the brain and being loaded in oligodendrocytes, as you find it in control tissue, control brains. And we don't think that this is only this iron from the oligodendrocytes which is then loaded into the microglia and macrophages; we think there are additional sources possibly from the vasculature.

MSDF

Very good, thank you.

[transition music]

Thank you for listening to Episode Forty-five of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is vice president of scientific operations.

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

[outro music]

[intro music]

Host – Dan Keller

Hello, and welcome to Episode Forty-Four of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.

This week’s podcast features an interview with Dr. Monika Bradl, who discusses animal models of neuromyelitis optica, NMO. But first, here are some of the new items on the MS Discovery Forum.

According to our curated list of the latest scientific articles related to MS, 69 such articles were published last week. To see the list, go to msdiscovery.org and click on Papers. We selected two of those papers as Editors’ Picks. One – on the use of MRI in NMO –included no fewer than 48 co-authors, a veritable Who’s Who of prominent MS researchers. The other editor’s pick, which had “only” 36 co-authors, was a large study providing strong evidence that disease-modifying treatment reduces disability worsening events in clinically isolated syndrome and early MS.

.

[transition music]

Now to the interview. Dr. Monika Bradl is an associate professor in the center for brain research at the Medical University of Vienna, Austria. I talked to her in her office about her work with animal models of neuromyelitis optica to probe what occurs in the early stages of the disease. She first describes why animal models are important.

Interviewee – Monika Bradl

NMO is a very rare disease, and so you have the problem that you get only very little pathological material, and so when you want to know what's going on at the very beginning of the disease you have to use animal models. And so our pioneer work there in the NMO field was to find out whether the antibody that characterizes about 80% of NMO patients, that's an antibody directed against aquaporin-4, water channel astrocytes, is pathogenic or not. And so what we did is that we injected this antibody then in experimental animals. When we had the animals without any additional CNS inflammation going on, they remained completely fine, and that was at that time a bit of a debate because people thought that the antibodies could enter the central nervous system anyhow.

But then it turned out that this failure of the antibody to reach the uninflamed brain had also predecessor in humans. There they had an NMO patient in Japan who was diagnosed with NMO, and when they found that he has pathogenic antibodies, they were first afraid because this patient was blood donor with the Japanese Red Cross, and so at that time then they stored serum samples of all the blood donors for quite some time, and they found out that this person had pathogenic antibodies already for more than 10 years without showing any signs of disease.

And so this was then the human patient correlated to what we found in our NMO animals, and what we then also saw is immediately when we make our CNS inflammation with CNS-specific T cells which break open the blood-brain barrier, then the antibody gets access to the central nervous system, binds to the astrocytes, and then induces two different type of killing procedures. So the astrocytes are then killed with either the help of complement or with the help of a mechanism that's called antibody-dependent cytotoxicity; so both of these mechanisms are then responsible for tissue destruction.

Interviewer – Dan Keller

Getting back to the Japan patient, did they also follow the recipients of that person's blood? It seems like this patient did not have that second hit which would allow the antibody to cause problems, but giving it passively to someone who already had the first hit might cause a problem. Did they look at the recipients?

Dr. Bradl

I'm sure they did, but there are no records about it to my knowledge. They might have been published in Japanese in some of these Japanese journals, but not in the international journals. But I'm quite sure that there was no immediate transfer of the disease with these antibodies because that would have made headlines. So one can conclude from that that this must have been harmless.

MSDF

And what animal models are you using?

Dr. Bradl We are using rat models, but there are other groups that are working in mice. We use Lewis rats and we think they are great because the rat complement works with the human antibodies, so it provides the help. And we have an NMs strain the Lewis rat which is extremely susceptible to all different types of autoimmune diseases, and so therefore we like rats and their CNS is larger and nicer. But people who work with mice, they also have advantages because they can use the entire transgenic zoo of knockouts or gene-mutated animals, and with this they can learn more about the contribution of individual molecules to the disease process.

MSDF

Now that you bring up the mice, are some mice more susceptible based on MHC than others; are some resistant?

Dr. Bradl There you have to consider one peculiarity of the mouse system. If you use mice, then you have the wrong complement system. So no matter what kind of inbred strain you use, you have to transfer human complement along with the human antibodies to get an effect, plus people who use the mouse model directly inject complement and antibodies into that brain to circumvent the blood-brain barrier. And when they do that, the MHC type of the particular mouse strain doesn't play a role.

MSDF

Is this using only passively transferred antibody, or do you try to raise antibodies by injecting antigen or modifying antigen?

Dr. Bradl

Yup. We desperately try to do so, but I have to say that this was not a real success story. So we first tried, as many other people did, to use just convention and normal aquaporin-4 as it is normally produced, or longer fragments of this, but obviously this does not work. And we now know that the antibody recognizes its target only if the aquaporin-4 is correctly folded within the same membrane. And only if this is the case, then there are three extra cellular loops which are available for antibody binding, and these three loops must be properly oriented and strictly optimally aligned in order for the antibody to bind. And this can only be hardly mimicked in the animal model just by immunization.

We then tried also to immunize with membranes of aquaporin-4 transfected cells, and there we got a little of antibody titer, but when we used these antibodies to stain tissue in order to find out whether they are good one, we saw much more staining than we would have liked, and so that means that the membranes are probably contain some antigens which were then, after immunization, targets of antibody responses. So this was so far in our hands a failure. And as far as I know, we are not the only ones that suffer from that. So there is currently, unfortunately, no model which works after immunization with aquaporin-4.

MSDF

Where do you go from here?

Dr. Bradl

Well, we are currently modifying our animal models to the extent that we study much more the T cell responses, and we also try to modify the B cell site, but this is a bit of a, let's call it easy way modification. Because we learned along the way that when we have a very, very, very good NMO IgG from a patient, we can work with very low antibody titers, and so that gives us a very nice animal model. And we also know that there are some NMO IgGs which make high titers in the patients but which are relatively lousy in animal models. So we learned from this that we just select and search for the best animal IgG for the model to transfer this; that's the B cell side. And on the T cell side, you'll find T cells in NMO lesions, but people had a hard time to get aquaporin-4 specific T cells.

So it was not quite clear whether one needs aquaporin-4 specific T cells at all for the formation of lesions, or whether any other activated T cell that recognizes different proteins in the CNS could do the job as well. So over the last few months, we now were really able to produce really highly pathogenic aquaporin-4 specific T cells which do the job and which guide lesions to sites where they are also seen in NMO patients. And so with this we were now able to really advance our model much, much more than we had done before.

MSDF

So these T cells you've generated, and these are directly cytotoxic?

Dr. Bradl

We are not dealing with CD8-positive or cytotoxic T cells, we are dealing with helper T cells. And these helper T cells, we know that they exist because the pathogenic antibodies of the patients have a phenotype that needs T cell help in their formation. But it was all the time unclear whether the T cells only help in antibody formation, or whether they also help in localizing lesions to the correct places. And now we have really for the first time the impression that we have a cell line that does exactly this.

MSDF

How do you translate what you're finding out in the animal models to the clinical situation? Is it developed enough now that you can make correlates?

Dr. Bradl

Well, that's a good point. I mean, when you look, for example, at our T cell work, then we observed in our animals that there are a large number of epitopes available for antigen recognition by T cells in the rat. And then it turned out that people observed the same thing in mice, and now we know it's also the same thing in humans. And then when you have so many different epitopes or so many different parts of a protein that can be recognized by the immune system, then you have to figure out whether all of them could give rise to pathogenic T cells or not.

And in the Lewis rat, for example, one knows that on myelin basic protein, there are two adjacent peptides which can induce very nice T cell responses, but only one T cell response is pathogenic and the other harmless. And so we initially were facing the same problem with our Lewis rats and the many different epitopes on aquaporin-4, and there we found out that in principle we can also rise T cell responses against many of these epitopes, but we have to use an enormous amount of T cells to get lesions in the CNS.

But with our new T cell line, now we know that we only have to use very few cells to get the lesion, so they are the dominant pathogenic T cells. And it's quite nice that in NMO patients with a very peculiar MHC phenotype – that's an MHC phenotype that's mostly seen Brazilian NMO patients – they recognize dominantly an epitope that's very close to ours, and they termed this also immunodominant epitope. And it could be that it's pathogenic as well, but there is not yet any proof for that in humans.

MSDF

Looking at aquaporin-4 as a target in NMO, do these cells just use it as a target to destroy the cell that it's on, or does it result in a pathologic process by inhibiting the action of the channel?

Dr. Bradl

There are reports about knockout animals where there is no aquaporin-4 available, also on astrocytes in the CNS. And these animals are apparently healthy under normal conditions, but they show a disease phenotype under conditions where there is tissue swelling going on; for example, under ischemia, and so they cannot cope with that properly. So that means the complete absence of this channel is also bad. Then there are currently two different groups of thinking in the scientific community. There are reports that antibodies can bind to aquaporin-4 and inhibit water flow through this channel, but there are other groups that could not reproduce it. And at the moment it could just be a matter of different antibody preparations or different test systems or different species, so this issue is not 100% solved yet.

MSDF

Anything we've missed or interesting to add on the topic?

Dr. Bradl

I think the only thing one can say is that since NMO is such an extremely rare disease and since this makes it necessary that people all over the world cooperate with each other, that leads to an enormously research-friendly atmosphere and an enormous willingness of the people to cooperate with each other, and so on all different types of subjects.

MSDF

How many patients are there?

Dr. Bradl

Well, when you look here in Austria, we have about 8 million inhabitants; there are 8,000 MS patients and approximately 80 NMO patients. And this frequency is more or less encountered throughout the world; it's a very rare disease.

MSDF

Very good, thank you.

[transition music]

Thank you for listening to Episode Forty-four of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is vice president of scientific operations.

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

[outro music]

[intro music]

Hello, and welcome to Episode Forty-Three of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.

This week’s podcast features an interview with Dr. May Han, who discusses issues related to following patients with clinically isolated syndrome. But first, here are some new items on the MS Discovery Forum.

We recently posted an article on a surprisingly strong association between a certain gene variant and non-response to interferon beta in people with RRMS. The study is a meta-analysis of three independent cohorts in Italy, France, and the U.S., and it comes from the labs of Philip De Jager and Filippo Boneschi. You’ll find this article by clicking first on News & Future Directions and then on New Findings.

This past week we published the latest in our series of data visualizations. This month’s visualization is a series of word clouds illustrating how key terms in the MS clinical-trial literature have changed between 1993 and 2014.To find this visualization, first click on Research Resources, then on Data Visualizations, and then on Word Cloud.

According to our curated list of the latest scientific articles related to MS, 30 such articles were published last week. To see last week’s list, go to msdiscovery.org and click on Papers. We selected one of those papers as an Editors’ Pick. It’s study of the association between depressive symptoms and walking ability in people with RRMS.

Are you attending the annual meeting of the Consortium of Multiple Sclerosis Centers in Indianapolis this week? If so, please come visit us at the Accelerated Cure Project’s booth. We’ll be demonstrating some of our latest data visualizations along with other features of the MS Discovery Forum. You’ll find the booth in the hallway close to the main entrance to the exhibit hall, and we look forward to meeting you.

[transition music]

Now to the interview. Dr. May Han is an assistant professor in Neurology and Neurological Sciences at Stanford University. I spoke with her about following patients with clinically isolated syndrome, as well as her approach to patients with MS across the course of their disease. But first, she addressed some unmet needs in MS.

Interviewer – Dan Keller

Dr. Han, you told me that we’re good at the diagnosis of MS in general, but still there’s a vast area that we don’t know about. What are some of those unmet needs?

Interviewee – May Han

So it’s been over 150 years since Charcot first described multiple sclerosis, and I have to say that we have come a long way in understanding and treating this disease. But as you have mentioned, there are still areas where we have no idea, there are gaps in our understanding of this disease. One of these areas that is clinically very relevant and is very challenging is in the day and age where we have a dozen disease-modifying therapies for MS patients, and yet we don’t have a good way, a scientific way of selecting the most effective therapy for a particular patient is what I find quite challenging in the clinics.

MSDF

What gives you clues or how do you approach this essentially algorithm of deciding where to begin and how to move on to other medications if the first one’s not working well?

Dr. Han

Currently, of course, we follow the guidelines. So for any relapsing-remitting patients, our logic is to go for the safest medication that we think are going to be most effective, which means we go with the first-line therapies. So we have the convention ABC drugs such as beta-interferon family of therapies and glatiramer acetate, plus the newer oral medications such as Tecfidera and fingolimod or Gilenya that we use for the first-line therapy; not a whole lot of science in choosing these medications for a particular patient, but what we would do is initially we would educate the patient about these disease-modifying therapies and then select the medication together with the patient to see what would be most appropriate and the patient could be most compliant for a particular medication.

To give you an example, certain patients have aversion to needles, in which case we go with the oral medications. We also have in mind what the preference of the patient, such as whether they could be able to follow it through for years on end with a particular medication. Ideally, we would like to have zero relapses or MRI activity when a patient is on a disease-modifying therapy, but as we all know none of these medications are 100% foolproof, and they can still have some degree of MRI activity or infrequent relapses on this medication. However, if a patient is clearly not responding to a therapy either in terms of not being compliant, being intolerant to the mode of administration, or if they’re having worsening disease activity, we would decide to go on to stronger medications or second-line of therapy.

MSDF

Do you initially discuss a plan of action, a stepwise pattern of medication prescribing, or do you wait until something needs to be changed to bring it up with patients?

Dr. Han

That is a very good question. I’m sure it varies among clinicians, but, however, I would like to paint the picture to the patient the best that I can. So, let’s say for example, if a patient who is a newly-diagnosed MS patient who has very few MRI lesions, I would discuss with them what the most appropriate medication could be. We would decide a medication and we would also give them an outline of what the followup plan would be and when we would be deciding to switch to a different therapy, and if so, which medications would be most likely appropriate for them, and also how we would monitor them. So by doing this, it gives the patient a better picture of their path and what to watch out for, and in my experience we have a better outcome with these patients.

MSDF

Do you find that once you achieve success in limiting relapses and lesions that the medication is fairly stable for a long time, or do you have to have an armamentarium that you keep moving through?

Dr. Han

So my model if a patient is responding to a medication, unless they have other side effects or reasons to switch, I would like to get the most mileage out of the medication as much as I can for a particular patient. However, if a patient, for example, has JC virus positivity, in which case even if they’re responding to Tysabri really well, there is a cutoff time point where we have to sit down and consider whether this patient should be switched onto a different medication to prevent the development of opportunistic brain inflammation such as PML, in which case what the next medication would be. And so we would sit down and talk the pros and cons; this conversation was started even before the patient was started on medication, but that would be the checkpoint.

MSDF

I suppose another aspect is do medications start to fail patients even after a long period of stability, or do they usually continue to be stable if the medication is working for some period of time?

Dr. Han

This is also a very pertinent question. MS patients, as we know, is very heterogeneous. Some of the patients, if they are stable on a medication, they would continue to do well on a medication for several years up to decades. However, some patients would have an initial improvement or stabilization of their disease, however in the later stages they would have worsening disease. And it is really unclear whether because their disease per se is getting worse or whether their body is rejecting the medication secondary to the immune response. And that is also one area that we should do research on to better understand this condition.

MSDF

When you say reject the medication, are you actually referring to an immune rejection such as with, say, interferon; I would think it would be less likely they would actually mount an immune response to a small molecule. Am I clear on that or not?

Dr. Han

I think we have quite a lot of information in terms of beta interferon therapies, because we clearly know that patients do tend to develop antibodies against beta interferon, especially the therapy. However, even that we don’t really know if all those antibodies are attacking the drug or whether they are just there. So just by finding the antibody alone is not enough to say that the patient is not responding to it; I think we need to use it hand-in-hand with the clinical response as well as the MRI activity.

Getting to the second part of your question whether there’ll be less intolerance or rejection to the therapy if it were small molecules, but I don’t think we understand at the cellular or molecular level. For small molecules there could be receptor down-regulation, there could be availability or cellular sequestration, or even the prodrug being converted to an active drug, or how the breakdown process occurs. So when a patient does not respond anymore to a medication, we just know that the clinical response is worse, and we don’t really know whether it is because the disease activity has worsened or other aspects, pharmacodynamic or kinetic aspects of the system has changed in such a way that they no longer respond. So, again, we do need to do more research to have a better understanding.

MSDF

You have called it MS comes in many different flavors. Have you found that any medications are particularly good for different constellations of symptoms, or is everything about equal no matter how they present?

Dr. Han

Very good question as well. I think in the experimental models people know that MS, or central system autoimmunity, can have a bias towards one type of inflammation as opposed to the other. For example, some would say that certain medications are better to treat Th1 as opposed to the Th17 type of inflammation, however in human beings there’s no clear-cut Th1 MS or Th17 MS. I don’t think people have done enough studies to clearly decipher the immune profiles of patients. So the answer is we don’t know.

MSDF

Finally, let’s talk about the need for biomarkers especially very early in the disease when someone’s presenting with CIS which may or may not become MS. Where does that stand and how acute is the need?

Dr. Han

The need is there, especially if you look at it from a patient who just had an initial attack. If you tell them that we don’t really know whether this is a one-time thing or whether you’re going to develop MS, and we’ll have to wait and see for three-plus years. So for these three years, the patient’s life is very much consumed by the “is it going to be MS” kind of question. And it does affect their physical-mental wellbeing as well as their quality of life.

I think we’ve come a long way with the advancement of the MRI studies in such a way that if a patient has MRI lesions together with the first-time attack, we could almost clearly say that this is going to blossom into MS. However, for patients who are radiographically clean and who just had one episode, it would be very, very helpful to have some kind of blood biomarkers to predict whether this could be a single event or whether it could be a central nervous system inflammatory disorder.

MSDF

You picked three years as a period of waiting, watching. Are they out of the woods after that, or how late can it blossom into full MS?

Dr. Han

It’s always a bell-shaped curve. There are patients who would declare themselves sooner than three years, there are also patients who would take several years before they have the second attack. I have one patient who had an initial attack of optic neuritis and nine years later she had the second attack. During that period, she had had MRI scans for three years which were clean. So, I guess, one is never completely out of the woods, but at the same time it is also not prudent to perform unnecessary tests on a patient.

So I think we have to focus on what is the safety net and pick a period of time, but at the same time it is very important to educate a patient to symptoms to watch out for, how to get help, and to work very closely with the primary care physician or a neurologist so in case the symptoms show up they will not be ignored or delayed to receiving treatment.

MSDF

Is there anything we’ve missed or is important to add? I’m sure it’s a gigantic field, but is there anything glaring that should be added?

Dr. Han

I would like to encourage people in the field to also focus on the secondary-progressive stage of MS. We know that relapsing-remitting MS patients with or without therapy eventually would end up having secondary-progressive MS, so it’ll be really important to decipher whether during the secondary-progressive stage there is no inflammation but only the early neurodegeneration, or how the immune system and the central nervous system interact and how we can change it, or at least modulate it, to either delay or to prevent neurodegeneration. The third area that I think is very important is to try to understand the regenerative aspects of the central nervous system.

As I have given you the example, if we have two patients who have had similar lesion burden or even lesions that are approximately the same in similar areas, a patient can be severely devastated, neurologically devastated, whereas the other may have minimal neurologic deficits. And we would always say that it depends on the brain reserve, or neural reserve, but we don’t quite know what it is. Is it the stem cells, is it the nervous system being more resistant to insult and how the immune system interacts with it? And I think this is also a big area that we should focus on, of course, to prevent further damage, but also once the damage is done to limit the damage and perhaps to regenerate it. And I think that people always have within themselves the ability to heal.

MSDF

Good, thank you.

Dr. Han

Thank you.

[transition music]

Thank you for listening to Episode Forty-Three of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is vice president of scientific operations.

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

 [outro music]

[intro music]

Hello, and welcome to Episode Forty-Two of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.

This week’s podcast features an interview with Dr. Lawrence Steinman, who discusses a surprising result involving amyloid, a molecule typically associated with destruction in Alzheimer’s disease, in an animal model of MS.

Our Drug-Development Pipeline includes continually updated information on 44 investigational agents for MS. During the past week we added 1 new trial and 16 other pieces of information. The drugs with important additions are dimethyl fumarate, daclizumab, glatiramer acetate, and natalizumab. To find information on all 44 compounds, visit msdiscovery.org and click first on Research Resources and then on Drug-Development Pipeline.

According to our curated list of the latest scientific articles related to MS, 50 such articles were published last week. To see last week’s list, go to msdiscovery.org and click on Papers. We selected one of those papers as an Editors’ Pick. It’s a meta-analysis of epidemiological studies of neuromyelitis optica, also called NMO or Devic’s disease. The conclusion of the meta-analysis is that there’s a high level of heterogeneity among the 9 studies that met the inclusion criteria. The prevalence of NMO in the studies ranged from 0.51 per hundred thousand in Cuba to 4.4 per hundred thousand in southern Denmark.

Will you be attending the annual meeting of the Consortium of Multiple Sclerosis Centers in Indianapolis next week? If so, please come visit us at the Accelerated Cure Project’s booth. We’ll be demonstrating some of our latest data visualizations along with other features of the MS Discovery Forum. You’ll find the booth in the hallway close to the main entrance to the exhibit hall, and we look forward to meeting you.

[transition music]

Now to the interview. I spoke with Dr. Lawrence Steinman, professor of neurology and neurological sciences, pediatrics, and genetics at Stanford University, who has a new twist on amyloid, this time in MS.

Interviewer – Dan Keller

Dr. Steinman, you have proposed that amyloid can be a protective molecule as well as what’s commonly viewed as a destructive molecule. How did you come upon this?

Interviewee – Lawrence Steinman

We came about it serendipitously or by accident. I had a graduate student and I thought I would give that student some low-hanging fruit, and the low-hanging fruit was to take the conventional animal model that we use for multiple sclerosis called experimental autoimmune encephalomyelitis – EAE. And when she put in these long peptides from an infamous protein named amyloid beta – A-beta – she put it into the animals with EAE at the time they were paralyzed, and I thought well, these are molecules that cause even more inflammation in the central nervous system, so they should make the disease worse, or perhaps they’ll have no effect and then we’ll have to think of another project for her PhD. So the student, Jacqueline Grant, came back and said, “Well, I gave the A-beta peptides and the animals are all better, they’re walking around.” And I first reacted, no, you must have confused the cages, let’s do it again. And when we did it again there was the same result, so then we were off to the races.

There was a second reason besides the low-hanging fruit description. May Han, my colleague, and I had reported the proteomics of MS lesions; so we took well-defined MS lesions, May cut frozen sections and then removed the lesion area with a laser tool, and then we trypsinized, fragmented the proteins, and used a modern technique, mass spectroscopy, to get the proteome, a list of all the proteins in the lesions. So amyloid proteins such as amyloid precursor protein and cal protein are found in the lesions themselves, so I thought that that was a second opportunity, a second foundation for doing these experiments in EAE; let’s see what happens when we augment, if you will, a naturally occurring protein found in the lesion to see perhaps what it’s doing. But, again, my bias, based on the dominant theory in Alzheimer’s disease is that amyloid was going to cause harm in MS as well as Alzheimer’s.

MSDF

In these experiments, the amyloid was injected IV so it seems to circulate, but does it get to the brain in these mouse EAE models?

Dr. Steinman

Actually, it does not get to the brain. We’ve actually put it into the brain directly to see if it would spread throughout the brain, and in our hands the molecules we’re working with do not spread. Most of these experiments showing a prion-like spread of amyloid is done in animals that are overexpressing the amyloid proteins in the brain so that they’re sort of tilting the balance to enhance spread if it’s going to occur, but we don’t get these amyloid molecules into the brain when we inject them intravenously, nor do we spread them around when we injected them directly into the brain.

MSDF

So if you’re injecting them peripherally, do you think that there is some direct effect, or do you think they’re acting through lymphocytes or other circulating cells?

Dr. Steinman

Well, we now know that there are at least two mechanisms. One is that when we are injecting them peripherally, these amyloid-like molecules, they go to sites of inflammation and this could include sites of inflammation within the brain. But remember, they’re on the vascular side of the lesion. And they act in a way like molecular sponges. The amyloid molecule is very sticky; in fact, when you try to work with some of the amyloid molecules, they’re like bricks, they stick to the walls of test tubes, and more importantly, they stick to each other and form these long, brick-like fibrils.

So what they’re doing when we put them into the circulation is they’re sopping up many of the inflammatory mediators that appear in the circulation during inflammatory diseases, including inflammatory diseases of the brain. These inflammatory mediators include the complement proteins and some of the famous apolipoproteins that we’ve heard about in reference to Alzheimer’s, we’ve heard the most about apolipoprotein E. So these amyloid molecules, when they’re in the circulation, actually stick and take away, precipitate away these inflammatory mediators. So I call it a molecular sponge.

There’s another set of mechanisms that we’re learning about that we’re able to use these amyloid proteins to do a couple of things to lymphocytes. One, it sets up a type 1 interferon response in lymphocytes. So the amyloid fibrils are a known trigger for the production of type 1 interferon, and type 1 interferon is actually beneficial for neuroinflammation; we have approved drugs. It’s doing another thing that we’re on the verge of publishing, but I’ll sort of give the headline without too many details; it’s setting up a type of lymphocyte that has a more regulatory function. So these are all rather unexpected roles for amyloid proteins.

MSDF

And you have done adoptive transfer of some of these lymphocytes and find similar effects?

Dr. Steinman

Yes. And the adoptive transfer experiments are very interesting. When we set up the system to produce a lot of type 1 interferon after we give an amyloid fibril, if the type of disease is what’s called the Th17 disease, the increased beta interferon actually worsens that, and if we create a disease that is called T-helper 1 – Th1 – then the type 1 interferon is beneficial. So we’ve engineered some amyloid structures so that they trigger less type 1 interferon, and when they trigger less type 1 interferon, then they work in both the Th1 and Th17 models. We published on that in the Journal of Experimental Medicine. But, again, even here with the type 1 interferon, the effect is nuanced and we can engineer these amyloid structures to be really beneficial and to take away the harm.

I wanted to say one thing, that clinicians and working scientists generally understand amyloid very well. Amyloid-beta that’s well known. Other amyloid proteins that people are, of course, familiar with are tau, prion protein, alpha-synuclein. But an amyloid structure is a general description of a protein that forms beta sheet, so the beta strand structure allows through hydrogen bonds the formation of what you should think of as a venetian blind, these monotonously parallel sheets that actually intercalate dyes, like Congo red or thioflavin T, so that when you shine polarized light on them they refract it in a polarized way. So we can make these structures, if you will, they’re organized nano particulars, to be more or less water-soluble, to be greater or lesser inducers of type 1 interferon. So there’s a whole armamentarium of very interesting amyloid structures that we can engineer to provide benefit in different situations.

Now what does this all mean for the Alzheimer’s hypothesis? And we’re doing an audio interview, so I’m sort of smiling wryly. I don’t want to get into that because we haven’t done the experiment in the amyloid-beta overproducing transgenic mice that have served as the model system to test whether various amyloid-lowering procedures will provide benefit, we just haven’t done that. And we’ve tried our particular approach in a number of other conditions ranging from stroke to EAE, as I said, to experimental heart attacks. And in the systems that we’ve studied, we see benefit.

MSDF

But as a further proof of concept of what you have found in the protective effect of amyloid, you’ve looked at amyloid precursor protein knockout mice. Is that right?

Dr. Steinman

Yes. Well, that’s a whole interesting story, and thanks for reminding me. So in a series of experiments that we have done and others have done, we first noticed that amyloid precursor protein knockout mice, they had worse EAE. Another person in Australia, Colin Masters, who’s actually one of the leaders in the field of Alzheimer’s research, looked at experimental head trauma, and in the amyloid precursor protein knockout mouse, they had a worse condition after head trauma that was alleviated by giving amyloid precursor protein in its soluble form. And then other people have shown that experimental encephalomyelitis is worse in prion knockout animals and in tau knockout animals.

We had been working with a protein called alpha-B crystallin, which is also an amyloid-forming protein, and we noticed that EAE was worse in the absence of alpha-B crystallin. So there’s a long series of experiments that loss of function, loss of the parent protein of these amyloid-producing molecules, leads to worsened inflammation, whether it’s EAE, head trauma, or somebody else did it in experimental heart attack. And we also did it in experimental stroke, so under a variety of conditions.

So this makes the argument even stronger, suggesting that amyloid structures when augmented can provide benefit and reduce inflammation, and when absent can actually exacerbate inflammation; so gain of function better, loss of function worse. So you have to look at the amyloid molecule as something that is not always harmful and pathologic. Whether it is the main culprit in Alzheimer’s, whether Alzheimer’s is an example of neuroinflammation, I leave it to people in that field because I really don’t want to take them on headlong at this point in time when we have all these fascinating results elsewhere. But I let the listeners draw their own conclusion based on the published work that I’m talking about, not only from my own lab but from other investigators all over the world.

One might want to think a little bit differently the next time one thinks about the deleterious effects of amyloid in Alzheimer’s, but I’m not going to be the one that takes on that massive scientific opinion, we’ll just have to see how it works out. I hope everyone’s been right over all these years because we certainly need some answers in that field. And if they are right, then we’ll have to integrate the kinds of things that we’re understanding about the role of amyloid proteins in other types of inflammatory conditions with a positive result in Alzheimer’s when it’s taken into the clinic. If it turns out that the experiments do not succeed in Alzheimer’s, then it will be easier to reconcile these different outcomes. But I think we’ll have to be patient; science doesn’t move as fast as some of us would like to have it move.

MSDF

What was the time course of seeing a result by injecting the amyloid in your EAE models?

Dr. Steinman

It’s very fast. When you inject the amyloid, it’s within 48 hours. If you stop giving the amyloid – we like to give it every day – if you stop giving it for a few days, the inflammation recurs, and that suggests that these amyloid structures are acting like a pharmaceutical. It’s not one of these situations that you sometimes see in science; you give the molecule once or twice and the disease goes away forever. This seems to be suppressing ongoing inflammation while it circulates, and when you take it away the effect is gone and the disease recurs, so that’s very interesting.

MSDF

The effect seems to be too quick for remyelination to be occurring as the answer, but when you give it chronically do you see remyelination?

Dr. Steinman

So far, we haven’t looked for long enough periods of time or with sensitive enough techniques. Your question triggers an experiment and we should really take a look at that. I would imagine that if you can abrogate inflammation that you’ll allow for remyelination if there’s anything left in the oligodendrocyte precursor to remyelinate itself, or if you need a little augmentation, it would be good to do a stem cell type of therapy under the protection of this kind of antiinflammatory approach.

MSDF

Are you planning any early human trials?

Dr. Steinman

Ha! I chuckle because this is a tough one to bring into the clinic. I’ve been funded by people who first scolded me for saying don’t take this too fast into the clinic, because I like to translate results. In this one, we’ll have to be more cautious than we might for other types of therapies.

MSDF

Is there anything important to add?

Dr. Steinman

I thought the questions were very comprehensive. And as you can see from where our matters stand now, there’s a lot of positive leads to pursue. And I think we’ll have to be cautious about translating in the fields of multiple sclerosis or stroke because of the infamy of the molecule I’m working with, but we’ll get there. Thank you.

MSDF

Thank you.

[transition music]

Thank you for listening to Episode Forty-two of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is vice president of scientific operations.

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

 [outro music]

[intro music]

Host – Dan Keller

Hello, and welcome to Episode Forty-One of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.

This week’s podcast features an interview with Diego Cadavid, who discusses trials of anti-LINGO-1 in MS. But first, a few updates on the latest developments at MSDF.

Our Drug-Development Pipeline includes continually updated information on 44 investigational agents for MS. During the past week, we added 3 new trials and 11 other pieces of information.  The drugs with important additions are dalfampridine, fingolimod, glatiramer acetate, interferon beta-1a, interferon beta-1b, naltrexone, and natalizumab. To find information on all 44 compounds, visit msdiscovery.org and click first on Research Resources and then on Drug-Development Pipeline.

According to our curated list of the latest scientific articles related to MS, 54 such articles were published last week. To see last week’s list, go to msdiscovery.org and click on Papers. We selected two of those papers as Editors’ Picks. One is a meta-analysis of mortality studies showing that excess mortality in MS relative to the general population has not changed over the past 50 years. In the other Editor’s Pick, Jagannadha Avasarala points out that 20% of patients who present with a symptom consistent with a diagnosis of clinically isolated syndrome do not meet radiological criteria on brain MRIs. Dr. Avasarala has contributed an essay to MSDF in which he discusses the consequences of this finding. To see his essay, go to msdiscovery.org and click first on News and Future Directions and then on Essays and Opinions.

[transition music]

Now to the interview. Dr. Diego Cadavid works at Biogen Idec, a pharmaceutical company involved in MS therapeutics. Our executive editor, Bob Finn, caught up with him in Washington D.C. at the annual meeting of the American Academy of Neurology, where Dr. Cadavid presented results of a phase 2 trial of an anti-LINGO-1 antibody called BIIB033 in which the antibody appears to promote myelin repair in the human brain.

Interviewer – Robert Finn

Dr. Cadavid, welcome.

Interviewee – Diego Cadavid

Thank you, Bob, for having us.

MSDF

First, what is anti-LINGO-1, and what does it target?

Dr. Cadavid

Anti-LINGO-1 is an investigation and treatment for a myelin repair. It targets a protein called LINGO-1 expressed in the myelin forming cells that normally inhibits the production of myelin. By blocking LINGO-1, we believe healthy cells actually make myelin and at the same time help patients with demyelinating diseases like MS.

MSDF

Tell me more about LINGO-1. Why this target makes sense in multiple sclerosis.

Dr. Cadavid

Yeah, so LINGO-1 is an inhibitor of myelination. So MS is a demyelinating disease, and it's well established that the majority of patients once they lose myelin they actually are not capable of repairing it. And the question in the field has been why? It's becoming clear that it's not because of a lack of cells; the myelin forming cells are there, but they're not making myelin. So one of the leading hypothesis is that there is a blockade of the ability of these cells to make the myelin. Biogen – more than 10 years ago – was looking for a molecules that could mediate that inhibition, and that's when they found LINGO-1. And through a series of experiments in animal models and in vitro, they showed that when you block LINGO-1 these cells actually differentiate and make myelin. Here we are more than 10 years later reporting the first results of an efficacy trial of anti-LINGO in humans. That's the RENEW study in acute optic neuritis.

MSDF

So tell me about the use of optic neuritis sort of as a model of MS.

Dr. Cadavid

Yes, we chose acute optic neuritis as the first efficacy trial because, first of all, acute optic neuritis is how many of them, as patients, actually initially present. They're healthy, living in the community, and so then they lose vision in one eye due to acute optic neuritis. In fact, during their lifetime, most MS patients will develop acute optic neuritis, so it is very relevant to MS. But also because it's the one part of the brain that is readily accessible. Through the pupil, we can actually image the neurons of the optic nerve. And using electrophysiology and something called visual evoked potentials, we can very accurately measure the function of this neuronal pathway. So it is not only relevant to MS, we have really good tools to investigate not only the disease but what anti-LINGO-1 may be doing to help the patients.

MSDF

But are there indications that anti-LINGO-1 has affects more centrally than the optic nerve?

Dr. Cadavid

So the optic nerve – we call it a nerve, but it is really not a nerve – it's a part of the brain. So anti-LINGO-1 is actually a central molecule. What we mean? It's really expressed only in neurons and in the myelin forming cells; it's not expressed outside of the central nervous system. So all the effects of anti-LINGO-1 are believed to occur centrally.

MSDF

Where is anti-LINGO-1 in the development process?

Dr. Cadavid

We are in the middle of drug development process, Bob, I assume you're asking me. We are in the middle of phase 2. We just finished the first of the two phase 2 trials called RENEW. These are results we are communicating at the academy this year. We believe the RENEW trial results showed efficacy on the primary endpoint: recovery of latency of the visually evoked potential. And we believe this is the first evidence that blocking LINGO-1, in fact, is leading to remyelination in the human brain, first episode of acute optic neuritis. So it's only approved for biology. At the same time, we are running a larger study in MS patients both relapsing-remitting and secondary-progressive. It is a longer trial, 22 months. That trial is fully enroll, ongoing, and we are looking forward to the results next year. The results of both trials will inform on the next steps.

MSDF

Is that a phase 2 trial, as well?

Dr. Cadavid

Correct. It's the MS trial; it's called SYNERGY, and it's a phase 2 trial. It is dose ranging. Unlike RENEW in which we only tested one dose, in the MS trial – SYNERGY – we are testing several doses.

MSDF

How is it administered?

Dr. Cadavid

It is a monoclonal antibody given every four weeks by an intravenous infusion.

MSDF

So you said that the results of this larger phase 2 trial will be available next year. Assuming that those results are favorable, what's the next step after that?

Dr. Cadavid

The final phase of drug development is what we call phase 3, which is when we actually run definite trials where the primary endpoint it's some meaningful clinical endpoint. For example, improvement in disability, slowing of disease worsening. So those phase 3 trials are usually longer and larger, and if the primary endpoints are met and the safety and tolerability is adequate, we file hoping for drug approval and to make this therapy available to patients.

MSDF

Four or five years?

Dr. Cadavid

Phase 3 trials are usually longer, and we don't know until we're there. But yeah, these are a longer part of the drug development process.

MSDF

Now assuming that the clinical trials do pan out – and maybe it's a little bit too early to ask this question, but I'm going to ask it anyway – how will anti-LINGO-1 be used? Is it going to be used early in the disease, late in the disease? The way other DMTs are used now continuously or to respond to a remission?

Dr. Cadavid

Ultimately, it will come from the results from the trials. But if you think about demyelination, it is a core component of MS. All forms of MS – from very early to very late – have a loss of myelin. So as long as there is ongoing or preexisting loss of myelin, we believe there is a potential for a remyelinating therapy like anti-LINGO to help the patients.

MSDF

Now you mentioned not only relapsing-remitting but secondary-progressive, and I'm sure you know there's a long history of things that have not worked well for progressive disease. Do you have a reason to believe that anti-LINGO-1 will be efficacious for progressive disease?

Dr. Cadavid

So, Bob, it is true that there really no effective therapies in SPMS right now. It is an area that we are focusing on anti-LINGO because we know there is extensive demyelination in secondary-progressive MS. Interestingly, there is a lot of cortical demyelination with relative preservation of axons and neurons. So we believe that if this drug is capable of repairing the myelin we could actually be able to help patients with SPMS. The phase 2 program includes patients with SPMS, so we obviously are looking forward to the results from the ongoing phase 2 trials to help us make decisions on next steps.

MSDF

Why not primary progressive?

Dr. Cadavid

Primary progressive MS is also under consideration. Right now we have to focus. Obviously what we learned from secondary-progressive MS will also inform us as to pursue primary progressive MS. We are aware there is a high unmet need, and we keep those patients at heart too.

MSDF

Just in terms of procedurally a technique why are you focusing on secondary-progressive before primary progressive?

Dr. Cadavid

So there are some practical reasons. One of them is that SPMS is viewed as closer to relapsing-remitting MS relative to primary progressive MS. So in the phase 2 trial, we have to try to keep some focus on the population. If we spread too much, it may become more difficult to actually interpret the data. There is a strategic reason as SPMS is closer to RRMS than PPMS is.

MSDF

Well, Dr. Cadavid, I've come to the end of my prepared questions. Is there anything I haven't asked that I should have asked or anything you'd like to add?

Dr. Cadavid

I like to finish by saying that the results of the RENEW trial it's really the first time we have seen evidence from the human brain that it appears possible to repair the myelin. This is a very important step in the field. There is a lot of work to do. But it is encouraging news, and we are happy to share this with the community. And Biogen is very committed to MS and to help patients who are living with this chronic disabling condition. So we welcome the news, and we also are ready to embrace the following stages of drug development, which are obviously very challenging.

MSDF

Well Dr. Cadavid, thank you very much.

Dr. Cadavid

Thank you, Bob, was a pleasure.

[transition music]

MSDF

Thank you for listening to Episode Forty-One of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is vice president of scientific operations.

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

[outro music]

[intro music]

Host – Dan Keller

Hello, and welcome to Episode Forty of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.

This week’s podcast features an interview with Raj Kapoor who discusses a clinical trial of the epilepsy drug, phenytoin, for MS. But first, a few updates on the latest developments at MSDF.

We posted an essay by Dr. Katie Lidster of the National Centre for the Replacement, Refinement, & Reduction of Animals in Research, a U.K.-based scientific organization. In her essay, she points out that Dr. Kapoor’s phenytoin study was made possible by the prior development of a refined mouse model of MS that is more humane than experimental autoimmune encephalomyelitis, which results in paralysis. To find Dr. Lidster’s article, go to msdiscovery.org and click first on News and Future Directions and then on Essays and Opinions.

Our Drug-Development Pipeline includes continually updated information on 44 investigational agents for MS. During the month of April, we added 9 new trials, we updated information on 28 trials, and we've added 42 other pieces of information.  The drugs with important additions and changes are alemtuzumab; BAF312; BIIB033, which is also called anti-LINGO-1; daclizumab; dalfampridine; dimethyl fumarate; fingolimod; glatiramer acetate; interferon beta-1a; interferon beta-1b; laquinimod; mitoxantrone; natalizumab; phenytoin; rituximab; RPC1063; and teriflunomide. To find information on all 44 compounds, visit msdiscovery.org and click first on Research Resources and then on Drug-Development Pipeline.

According to our curated list of the latest scientific articles related to MS, 42 such articles were published last week. We selected two of them as Editors’ Picks. One is a review of the role of microRNA in MS. The other is an analysis of the cost of MS drugs in the U.S. This study reports several startling facts. For example, first-generation MS drugs, which cost $8000 to $11,000 annually when they were first released, now cost $60,000 a year. And disease-modifying therapies cost two to three times more in the in the US than in comparable countries. This study ties in nicely with our interview with Dr. Kapoor. Phenytoin has been off patent for many years and is dirt cheap. Good news for MS patients? Maybe not. Paradoxically, phenytoin’s low cost may mean that it will never be fully developed for use in MS. To see our curated list of recently published papers, go to msdiscovery.org and click on Papers.

[transition music]

Now to the interview. Dr. Raj Kapoor is a neurologist at the National Hospital for Neurology and Neurosurgery in London, England.

Interviewer – Robert Finn

Hello, this is Bob Finn. I'm at the American Academy of Neurology meeting Washington, D.C., and I'm talking with Dr. Ray Kapoor, who's presenting a very interesting study on a trial of phenytoin – also called Dilantin – in optic neuritis. Dr. Kapoor, welcome. So my first question is why phenytoin and why optic neuritis?

Interviewee – Raj Kapoor

So phenytoin we use because it works as a sodium channel blocker, and this is based on years of experience and validation in animal models over the years about how neuroprotection could be achieved in MS. And it turns out that sodium channels are quite important for neurodegeneration in the setting of inflammation. And work in London that we've done, work in Yale has validated animal models that say that if you block sodium channels you can achieve neuroprotection. So why phenytoin? Well that comes down to why optic neuritis? We wanted to test sodium channel blockade in a relapse. And optic neuritis has a lot of advantages because you can study the visual system in so many ways. So why phenytoin? Because we think there's a window of opportunity, and a relapse degeneration occurs pretty rapidly. You need to treat quickly to switch off the mechanisms of neurodegeneration. And phenytoin has the advantage that we can load it very quickly and achieve therapeutic levels. So we have here a model of neuroinflammation and neurodegeneration, which we can study using multiple techniques. And we have a drug that we can load and inhibit those mechanisms quickly.

MSDF

I find it fascinating that optic neuritis, which is one of the many symptoms of multiple sclerosis, can be used as a model for multiple sclerosis itself.

Dr. Kapoor

The important thing there is it's part of the model. And the key is that we have – in MS – two processes going on. We have inflammation flaring up and leading to relapses like optic neuritis; and then, there is perhaps an allied or even a second process going on, which is the slow grumbling degeneration that leads to progression of disability. Now, we've studied both, but what we're focusing on in this study is that acute process that leads to relapses, you know, attacks which occur from time to time. I mean they're quite important in themselves because they don't always recover. We know that with every attack – even if there's apparent recovery – there is underlying damage to the nervous system. So to protect the nerves in any case is self-serving; it's a good idea. But what we are hoping is that this may even be a key to preventing progression, and that would really be a worthwhile target.

MSDF

So you say you chose phenytoin because of its effects as a sodium blocker. What's the connection between sodium and neurodegeneration?

Dr. Kapoor

What we found many years ago was that in areas of inflammation there can be nerve damage. And the inflammation drives nerve damage through a number of pathways, but one of them is that it actually indirect leads to sodium accumulation inside the nerve fiber, the axons. This has been well worked out in ischemia, as well. So sodium enters axons; it can't leave through the normal sodium pump because they're metabolically inhibited by the inflammation itself. And the sodium exchanges with calcium. So there's a sodium/calcium exchange in the membrane of nerve cells, and if you load them with sodium then sodium has to get out and gets out by driving the influx of calcium, and that's dangerous; that kills axons. So the whole process can be inhibited by inhibiting sodium entry. Now there's another thing that's very important, which is in acute inflammation one of the things that drives it is microglia, activated microglia release chemicals such as nitric oxide, which in themselves drive the whole inflammatory damaging cascade. But it turns out – and this is work from Yale – that actually the microglia themselves have sodium channels, and that their functioning can be inhibited by inhibiting those same channel. So what phenytoin is doing is it's actually inhibiting not only the cascade that damages the axons but is actually inhibiting the cells which are driving the inflammation and causing the damage in the first place.

MSDF

Now, is there any indication that phenytoin may be working in this way more centrally than the optic nerve?

Dr. Kapoor

It's very unlikely because the mechanism that we've testes is really something well characterized as inflammation within the optic nerve. And we are measuring the damage and the effects of treatment by actually imaging the retina looking at retrograde degeneration from the optic nerve lesion. So I think it's very unlikely given the timescale – you know, we're treating within a couple of weeks of onset, we're having a readout within six months – that it's doing anything other than what we're asking of it, which is a readout of what's going on in the optic nerve and retina.

MSDF

If I understand you correctly, even if this is working exactly the way you want it to be, it's not going to be doing anything for people with central damage. Is that correct?

Dr. Kapoor

Well I think the thing to understand here is it may do in MS where damage is happening everywhere. This is really a proof of concept. We've tried our very best to isolate the damaging process and to work out whether the theory works. So yes, there may be more general implications, and we think there probably are. But it's important to note that really what we're doing here is choosing a very clearly defined model to test the hypothesis.

MSDF

Now one of the advantages of phenytoin is that it's generic; it's dirt cheap. But is that a liability, as well?

Dr. Kapoor

Yeah, this is a very important point. So we're talking here about this whole issue of repurposing drugs. And we think that there may be many different drugs on the shelf which may have a role in treating diseases like MS. Now for us that was an advantage. This is an investigator led study, and it was funded by charitable means from the National MS Society and UK MS Society. So that's an advantage because the drug is really cheap. But of course, in terms of development, the commercial reality is that there's very little money in this. And so to take this further, it makes it harder not to have a drug that makes money.

MSDF

So what's the solution to that problem?

Dr. Kapoor

We don't know. I mean there are lots of ways that we're taking this forward. I mean you may know that there is a thing called the Progressive MS Alliance, which is an international body of MS societies, which is trying to work its way through questions exactly like this establishing industry relations. And it may be that they're a scope for industry to step in. And governments step in sometimes. I mean in the U.K. we have a trial running at the moment which is using funds from government to do a moderately sized Phase 2/Phase 3 trial of neuroprotection. So I think, actually, this all depends on the results. If the results are good, then we hope that either through industry or through government or, indeed, through charitable means there may be a way through. Just to get back to your question, I think that, you know, repurposing is a problem because clearly the commercial angle is far less prominent.

MSDF

Is one possible solution to find a drug that's still under patent?

Dr. Kapoor

Indeed, that would be a remarkable thing to do. But of course, a trial in the beginning would then need commercial collaboration. But certainly that's an angle.

MSDF

So assuming that your research is confirmed and extended and phenytoin proves to be truly neuroprotective, when in the course of MS is it likely to be useful?

Dr. Kapoor So by definition, phenytoin is going to be useful for relapses. The idea that relapses sometimes leave damage and that a drug like phenytoin or phenytoin itself prevents some of that damage speaks for itself. The real question, though, comes down to whether progressive MS is also driven by similar mechanisms. We did a trial of lamotrigine, which is another sodium channel blocking anticonvulsant, and published the results about five years ago now. And that trial was reportedly negative for its primary outcome, which was brain atrophy; could we reduce the rate of loss of brain volume. I suppose what we've done is to go back to that trial and look at positive signals there because after all the question is do sodium channel blockers prevent progressive MS or prevent progression? And in fact, it turns out that there was some remarkable positive signals in that trial. So I have the knowledge that phenytoin should be useful for relapsing MS. But I also have a hunch that it may be useful for progressive MS, as well.

MSDF

Now there's a flipside to the fact that phenytoin is so easily available, and that is that physicians listening to this podcast or to other news reports may consider prescribing it off-label. How would you counsel somebody considering that?

Dr. Kapoor

I think it's difficult for somebody to use phenytoin in that way because the way the trial was designed was to treat people in a very narrow window after the onset of a relapse. Now people may say well, you know, the next time I see a patient who has a relapse, you know, can't walk or the vision is affected I will immediately prescribe phenytoin. The difficulty I have there is that this remains a very attractive study but hasn't proved the point. And phenytoin is not without its side effects. You know, I'm always somebody who's evidence led, and so I would counsel against using drugs without even further evidence. This is one Phase 2 study after all. I think the temptation will be there nevertheless.

MSDF

And if a physician falls to that temptation, what should he or she look for?

Dr. Kapoor

Well again, this is the point. We have shown a concept works. You know, we have shown that phenytoin, by a number of measures, prevents nerve damage. I think the difficulty – and I need to be very clear about this – is that with acute optic neuritis where vision generally recovers we didn't see better recovery with phenytoin. So again, perhaps another answer is that if I treat somebody with a relapse with phenytoin I'm not really sure that I may be protecting nerves, but am I producing a better outcome? So that may be another reason to say let's wait for a better drug or a better trial.

MSDF

That's a very good point. So is there anything I haven't asked that I should have asked, or anything you'd like to add?

Dr. Kapoor

No, I think that really the way I want to convey the result is that it's a robust result. I mean what I'll be presenting is that on a number of measures the drug worked. I think it worked with a modest amount of success. I see this is opening a door. I don't see this as the final answer to a problem. You know, if you think about it, we've been looking for a long time for a neuroprotective drug in MS and a strategy. And I think this is opening a door, which I think needs to be opened a lot wider.

MSDF

Dr. Kapoor, thank you very much.

Dr. Kapoor

Thank you. 

[transition music]

MSDF

Thank you for listening to Episode Forty of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is vice president of scientific operations.

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

[outro music]

[intro music]

Host – Dan Keller

Hello, and welcome to Episode Thirty-Nine of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.

This week’s podcast features the second part of our interview with Joseph Berger of the University of Pennsylvania. But to begin, a couple of updates.

Last week we told you about our Drug-Development Pipeline, which includes continually updated information on 44 investigational agents for MS. Since last week’s podcast we added two new trials, we updated information on 10 other trials, and we added 10 other pieces of information. The drugs with important additions and changes are dimethyl fumarate, fingolimod, glatiramer acetate, interferon beta-1a, interferon beta-1b, and phenytoin. To find information on all 44 compounds, visit msdicovery.org and click first on Research Resources and then on Drug-Development Pipeline

Two weeks ago we described how we curate a weekly list of all newly published scientific papers on MS and related disorders. Last Friday’s list included 53 papers. We selected two of them as Editor’s Picks: One is a Cochrane meta-analysis of dimethyl fumarate – trade name Tecfidera – for treating MS. The other is a study from Paul Tesar’s group at Case Western Reserve University. That study, which appeared in Nature, is entitled “Drug-based modulation of endogenous stem cells promotes functional remyelination in vivo.” To find the full weekly list and the Editor’s Picks, click on the Papers tab at msdiscovery.org.

[transition music]

Now to the interview. Dr. Joseph Berger is a professor of neurology at the Hospital of the University of Pennsylvania. In part one of his interview we talked about risk of progressive multifocal leukoencephalopathy. This week, Dr. Berger discusses diagnostic dilemmas in MS.

Interviewer – Dan Keller

Dr. Berger, how do these present, and what are some of them?

Interviewee – Joseph Berger

They’re legion, actually. There are a lot of different diseases that can look very much like multiple sclerosis both in terms of the history and physical examination as well as in terms of the radiographic findings. And the question is, do you want to avoid treatment that is not very helpful and expensive? You know, once you’ve made a diagnosis of multiple sclerosis you tend to put the patient on a disease-modifying therapy that they would remain on for the rest of their lives. And there’s an expense and some risk depending on what you put them on, associated with that. Secondly, there are diseases that, if you miss the diagnosis, these are diseases that can be aggressive in and of their own right, and if you’ve misdiagnosed it there’s a concern that disease may go on and create its own problems for the patient. So there are a variety of reasons why you want to ensure that what you’re dealing with is truly MS and not one of the MS mimics.

Among the common MS mimics, one that we’ve had increasing experience with in the recent past, is neuromyelitis optica. So, neuromyelitis optica was a disease that we lumped together with multiple sclerosis, but we’ve realized recently that not only is the pathogenesis different than multiple sclerosis, it being a humoral immune disorder, but that the therapies that we employ for multiple sclerosis may actually aggravate neuromyelitis optica. So that’s a common concern and one of the reasons why we frequently obtain neuromyelitis optica antibodies in patients, particularly when they present with optic neuritis or transverse myelitis, and certainly when they present with both of them.

MSDF

That would be aquaporin-4 antibodies?

Dr. Berger

That’s correct. It’s an aquaporin-4 antibody, but not everybody with neuromyelitis optica has the aquaporin-4 antibody that’s demonstrable. A certain percentage of them have what appears to be an anti-MAG antibody, and others we simply don’t know what the antigen is. And that’s being worked out. So there’s this whole spectrum of neuromyelitis optica that you certainly want to sort out from multiple sclerosis. But there are also a wide variety of other illnesses that can look like multiple sclerosis. In fact, if you take any broad classification of diseases – infection, vascular, neoplastic, toxic, metabolic, genetic, etc. – if you do that and say, are there diseases in these categories that can appear like multiple sclerosis and be mistaken for multiple sclerosis, there are. So every single one of these broad categories can have within it a disease that can be mistaken for multiple sclerosis.

MSDF

Would they be mistaken for multiple sclerosis on many measures or mainly signs and symptoms or is it radiologic on imaging? How do you sort out this kind of gamish of different diseases and how they present, and really nailing down an MS diagnosis, not even considering a diagnosis of what else it could be?

Dr. Berger

So it can be enormously difficult to do so. And I’ll give you some examples from my own practice. I have, for instance, seen individuals with a disorder called hereditary spastic paraparesis where you were unaware of their hereditary nature of their disease. And the patient has come in with a progressive myelopathy. And you say, well, could this be primary progressive multiple sclerosis? And could be extraordinarily difficult to sort out, particularly if they don’t have common mutations, and they don’t have a family history. And you say, well, which is it? The spinal fluid can be very helpful in that regard.

The MRIs can be very helpful in that regard, but not always. I’ve seen individuals who’ve had vascular disease where the MRI abnormalities have looked very much like multiple sclerosis. They’ve had recurrent episodes of neurologic symptoms be it numbness or weakness or visual problems, and it be mistake for MS. I’ve seen individuals with intravascular lymphoma, a rare disease, but one where they’ve presented with both clinical picture and MRI that looks very much like multiple sclerosis.

Although we have good diagnostic criteria, there is no single test that tells you that this is MS. But there are times when all of us, even the very best clinicians, scratch our heads when a patient’s reappeared in the office; nothing new has happened to him. Ten years have elapsed, and you say to yourself, did they really have multiple sclerosis? So, again, it’s a matter of comprehensive history and physical; the appropriate radiographic studies; looking at the spinal fluid when that’s indicated; and doing the appropriate laboratory studies to rule out things that may mimic multiple sclerosis.

MSDF

Is that why there is a diagnosis of CIS? If it never returns, then it was CIS?

Dr. Berger

I guess one could say that, but I use the term CIS to mean the very first episode of multiple sclerosis. So when I label somebody with CIS, I already believe that they have multiple sclerosis. I think that if they have CIS in the absence of any radiographic findings, I’d be unlikely to label them CIS. CIS to me is in the continuum of MS, so you have CIS, relapsing/remitting multiple sclerosis, secondary progressive multiple sclerosis. So that’s how I use the term.

MSDF

Can you definitely rule in or rule out multiple sclerosis?

Dr. Berger

I think that there are probably rare instances where people fulfill all the criteria for multiple sclerosis. And at the time of autopsy you say, how about that? That wasn’t multiple sclerosis. There’s an old expression in medicine that you can never be a 100% certain. You can never have a 100% certainty. So I think that you do the best you can. And I think that probably the rate’s 99% or better, but in these people fulfilling the criteria that have been established. However, you can never be entirely certain.

And it is not that uncommon in my practice, and I’ve been practicing medicine nearly 40 years, where an individual has presented the office after a long hiatus. And the chart is unavailable to me, and they come in with a diagnosis of multiple sclerosis, and I say, who made the diagnosis of multiple sclerosis in you? And they go, you did, Dr. Berger. So I think go down to the cave where they keep the charts that are over seven years old only to find out that they had all the criteria for multiple sclerosis; that they had oligoclonal bands, and they had hyperintense signal abnormalities on their MRI, and they had relapsing symptoms, but, you know, over the course of the last 10 years they’ve had little. And you scratch your head and say, geeze I wonder if this is truly MS?

There are probably people who carry this diagnosis, and there’s literature on it, that carry it incorrectly.

MSDF

Those criteria, even though it never turned out to be MS, satisfied a diagnosis of MS. When you see something like radiologically isolated syndrome, do you work it up for MS, or only once it presents later does it become MS?

Dr. Berger

This is a very difficult question, and we see this with some regularity, that is, the individual that has hit his head in a car accident or developed a headache that somebody’s decided to do an MRI on. And they come in with an MRI that looks all the world like a patient with multiple sclerosis, yet they have no symptoms and no signs on physical examination that is suggestive of multiple sclerosis. And the question then becomes, what do you do with them?

There’s currently a study in which that question is being addressed. However, I will tell you what I do, currently. I do look for multiple sclerosis. I look for lesions in their spinal cords because I think that if they have that, the prognosis can’t be good, and I would likely start somebody with lesions in their spinal cord, who I’m convinced has MS, on a disease-modifying drug.

I look their spinal fluid. And I look at their spinal fluid for oligoclonal bands, and, if I see that, I’m increasingly convinced that that’s what we’re dealing with. And I would be inclined to treat those people as well. Now whether I’m doing the right thing or not, I don’t know, but for others in whom there are no spinal cord lesions, there are no signs or symptoms, and the spinal fluid is pristine, I’ve elected to wait. That is not necessarily the consensus among the MS community. That’s simply how I practice, currently.

MSDF

People don’t need oligoclonal bands to have MS, though, do they?

Dr. Berger

No, not at all. So, we certainly see a fair number of people – and it depends on the study – who have pristine spinal fluids. That means no oligoclonal bands, no cells, no increased protein, no elevated myelin basic protein or IgGs who still have multiple sclerosis.

MSDF

What about fatigue as an initial symptom of multiple sclerosis? A lot of people have fatigue – tiredness. Is there a way to differentiate the fatigue of multiple sclerosis from just being tired or a sleep apnea or an insomnia or they just don’t feel good?

Dr. Berger

Well, I think your history is very helpful because the sleep deprivation and excessive daytime sleepiness is not the same as the fatigue that people with MS report. The fatigue that people with MS report is akin to the fatigue that one experiences when they have a viral illness. So when you have the flu you go, oh man, I just can’t get out of bed. I feel terrible. And that’s precisely what the people with multiple sclerosis have. And what’s so interesting is how common it is. So it’s been said to be the greatest cause of disability in the MS population. It’s an acceptable cause of disability; not blindness, not incoordination, not weakness, but fatigue.

And it’s curious, when I practiced in Kentucky, I had a number of patients who were wheelchair-bound, had very poor vision or had double vision because of paralysis ocular palsies, who went to work every single day. And then I had patients that looked as healthy as you and I, and they were on disability. And I said, well, why is it that you can’t work? They said, I’m just too fatigued. I can’t do anything. It’s affected everything.

So the fatigue is different, and getting back to the frequency of it, so in individuals who have been diagnosed with multiple sclerosis, and I was part of this study, if you look at large numbers of individuals diagnosed with MS or who are on disease-modifying drugs for MS and go back and look at their medical records prior to the time of the diagnosis, you will see that about a third of them had been labeled by their family physician or their internist as having one of two diagnoses: chronic fatigue syndrome or fatigue and malaise. They’re the only two diagnoses with fatigue in them that you could put into the ICD-9 classification.

So, this is striking that so many individuals have fatigue recognized, yet it’s an advance of their having any neurologic symptoms that were believed to be the consequence of multiple sclerosis. It’s not to say that they didn’t have them. You know, it might have been some transient numbness or transient tingling or slight weakness that went away that nobody ever thought was due to multiple sclerosis. So that we don’t know about. But what I can tell you is that prior to an established diagnosis of multiple sclerosis, roughly a third of individuals have been labeled by their family physicians with fatigue.

MSDF

It’s interesting that you make the analogy between this sort of fatigue and that with a viral illness like the flu. Could this be a prodrome telling there’s an inflammatory process going on? I mean, is there interferon release or are there other mediators that seem to be unique to this kind of fatigue?

Dr. Berger

I would like to think that that’s the case. I would like to think that this is due to the very same cytokines that cause the fatigue that’s associated with viral illness. That’s not been convincingly demonstrated, although it’s been proposed. I think it makes a lot of sense. Coming full circle, eventually, although most of my colleagues classify multiple sclerosis as an autoimmune disease, there must be a trigger for the autoimmune disease. And my own belief, coming to this from virological angles as opposed to coming at it from an immune angle, is that there’s probably some infectious origin.

One of the things that’s so striking is the association between Epstein-Barr virus and multiple sclerosis where virtually every adult patient with multiple sclerosis has evidence serologically of having been exposed to Epstein-Barr virus. Now I’m not saying that that’s necessarily the cause, but in some way it must contribute to the development of the disease perhaps in a way that low vitamin D levels contribute to the genesis of the disease.

MSDF

Is there anything you’d like to add about diagnostic dilemmas or any kind of a mental framework for approaching this sort of thing, in nutshell?

Dr. Berger

Yes. The one thing that I would say is never be too confident. Never be too confident. I found that my highest confidence levels were right before I took boards in neurology, which was a long time ago. And I thought I knew everything. And the more I practice neurology, the more humble I’ve become in terms of establishing diagnoses and selecting right therapies for patients. So I always have a healthy skepticism. I have a healthy skepticism of things that I feel certain about. And when patients represent to office I always question myself, particularly if there’s something that doesn’t fit with the diagnosis. And I think that that’s good advice to anybody practicing medicine.

MSDF

Very good! Thank you.

Dr. Berger

My pleasure.

[transition music]

Thank you for listening to Episode Thirty-Nine of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is vice president of scientific operations.

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

[outro music]

[intro music]

Hello, and welcome to Episode Thirty-Eight of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.

This week’s podcast features part one of a two-part interview with Joseph Berger of the University of Pennsylvania. But to begin, we’d like to tell you about MSDF’s Drug-Development Pipeline.

Twelve drugs are currently approved in the US for the treatment of MS, but there are many more drugs in various stages of clinical and pre-clinical development. We’re keeping daily track of 44 of them in our Drug Development Pipeline.

To visit the pipeline just go to msdiscovery.org and click on Research Resources, and then Drug-Development Pipeline. You’ll find a finely detailed, fully referenced, and easily searchable database of all 44 of those drugs. The database includes details on each drug candidate’s physiology, its progress through pre-clinical and clinical trials, and its regulatory and commercial status.

Science journalist Heather McDonald has managed this database since its inception, and she updates it continuously, whenever new information becomes available. In just the last week, for example, she added one new clinical trial to the database, she updated information on two other clinical trials, and she added 5 other pieces of information. The drugs with important additions and changes were dimethyl fumarate, fingolimod, glatiramer acetate, interferon beta-1a, interferon beta-1b, mitoxantrone, natalizumab, and RPC1063.

[transition music]

Now to the interview. Dr. Joseph P Berger is a professor of neurology and Chief of the MS Division at the University of Pennsylvania in Philadelphia. In part one of our discussion with Dr. Berger, we’re talking about the risk of progressive multifocal leukoencephalopathy (PML), a rare but serious brain infection that occasionally arises in people being treated for multiple sclerosis.

Interviewer – Dan Keller

The topic of quantifying risk and mitigating risk comes up with certain immunosuppressive drugs, notably natalizumab in MS but also with other drugs as well in other conditions. What are some of the confounding factors? Why is this not an easy thing to approach?

Interviewee – Joseph Berger

Well, it’s not easy because it’s so unpredictable. Nobody would have thought that natalizumab would have uniquely predisposed to the development of progressive multifocal leukoencephalopathy. In fact, when natalizumab was introduced, if one would have attempted to predict what would have happened, you might have said, well, we’ll see a wide variety of opportunistic infections of the central nervous system, since this is a drug that prevents the neural immunosurveillance that is necessary to prevent these diseases from occurring. However, that’s not what we see. We don’t see the opportunistic infections of the central nervous system that we see in the AIDS patient; for instance, things like cryptococcal meningitis and toxoplasma and tuberculous meningitis, it simply doesn’t happen. What we see, on the other hand, is this unique increased risk for the development of progressive multifocal leukoencephalopathy. This was an entirely, in my mind, unpredictable event. I suspect that this is true of many of the other drugs that are now coming to market; that our experience with them is limited, they have what we think is a well-defined effect on the immune system – they’re not broadly immunosuppressant – yet our knowledge of the immune system is such that we don’t understand fully the downstream effects they have. And it’s only after we’ve used these drugs for a number of years do we have a comfort level with what sort of risks that are engendered by their use.

MSDF

But it’s not unique to natalizumab; other drugs can induce this whether in neurologic conditions or even rheumatologic conditions. Is that right?

Dr. Berger

Yes. In talking about PML, that is true that there are other drugs that carry black box warnings for the development of PML; however, there’s something unique about natalizumab and another drug that is somewhat related to it and now off the market called efalizumab, which was a drug which went by the name of Raptiva and was used for the treatment of psoriasis. So there are drugs that uniquely increase the risk of PML and there are those that marginally increase the risk of PML, and one shouldn’t conflate them. And though a drug carries a black box warning for PML, it doesn’t necessarily mean that the risk is the same as it is with another drug that may also carry such a warning.

And let me explain this a little further. If you look at natalizumab and you look at efalizumab, those are drugs that have been used for conditions that had never previously been associated with progressive multifocal leukoencephalopathy. So despite the fact… And natalizumab, as you know, is used in the treatment of MS and used in the treatment of inflammatory bowel disorders, in particular Crohn’s disease, efalizumab used in the treatment of psoriasis; these are autoimmune diseases. And prior to the availability of these compounds, we did some aggressive immunosuppressive therapies in the treatment of these diseases. We would treat them with drugs like Cytoxan and azathioprine and high-dose steroids; a wide variety of things were employed. Yet until the PML experience with natalizumab and efalizumab, we had never seen PML in the setting of multiple sclerosis, in the setting of inflammatory bowel disease, or in the setting of psoriasis. So that tells you that there’s something unique about the drugs that we’re using and that it’s not necessarily the underlying condition that is responsible.

The second is when you start the drug, you do not see PML develop immediately; it takes some time. So the experience with efalizumab was three or more years, the experience with natalizumab is typically 12 months; actually the vast majority of cases – over 80% - have been on natalizumab for 24 months, so they’re on the drug for a long time. The shortest latency from initiation to the development of PML has been a single case in which it developed within eight months; everything else is 12 or more months. So what is that telling you? That tells you that the drug is doing something fundamentally to overcome the barriers to the development of this disease and that it’s not simply opening up a gate and letting the horses out; it’s doing something to the pathobiology of the disease.

And then lastly, the incidence with which we see PML with natalizumab – and presumably with efalizumab, although the numbers were much smaller – is extraordinarily high in the appropriate context. So for natalizumab, the risk of developing PML, provided you’re on the drug for two years, you’ve seen prior immunosuppressive therapy, and you’re JC virus antibody-positive so that you have been exposed to the virus that causes this disease, if you have all three of those, your risk is on the order of 1 in 90 or thereabouts. That is a risk that is commensurate with what we see with HIV-associated PML, so it’s very, very high.

However, if one looks at these other drugs which I have called Class 2 agents in several papers now; drugs like rituximab, also a monoclonal antibody though directed against CD20, drugs like brentuximab vedotin or mycophenolate mofetil – which is CellCept – those drugs, too, carry black box warnings for the development of PML; however, the setting in which PML occurs with their use is almost always with a condition that already predisposes you to the development of PML. So with rituximab, for instance, it’s seen with lymphoproliferative disorders, or with transplantation, or with autoimmune diseases in which PML had already been described long before the use of rituximab for the condition. And the same is true with these other drugs.

The second is there’s no latency to the development of the disease, so this is strictly a stochastic event; you may start rituximab today and in two weeks’ time develop PML. There’s no way that somebody’s developed PML in two weeks’ time. What that indicates is that individual was predisposed to developing PML, that virus was already in their brain, it was percolating there, your immune system was suppressing it adequately so it wasn’t expressing itself. And now you’ve done something, you’ve tweaked it a bit and the PML is now expressing itself because you’ve introduced the drug, but the drug fundamentally is not changing the pathobiology of the disease.

Lastly, although we do not have good figures on this, but the best data that I have is that we’re talking about orders of magnitude lower risk with these other drugs. So rituximab, for instance, the risk is probably on the order of 1 in 30,000, or something to that effect. That compared to 1 in 90 when you have all the risk factors that I described with natalizumab. So we’re talking orders of magnitude difference. So I’d suggest that we avoid conflating these drugs when talking about PML risks, and I think that this is something that is generalizable for other risks; I mean, PML is just one risk, but we see other infections and other things that have occurred with other drugs that we’ve employed tweaking the immune system, and I don’t think that one should necessarily put all these drugs that cause these things in the same boat.

MSDF

These drugs that are used in other conditions that do in themselves predispose to PML, when they’re used in MS which as a disease does not, on its own, predispose to PML, these same drugs – azathioprine, cyclophosphamide, mycophenolate – add to the risk when you give natalizumab?

Dr. Berger

That’s what it looks like. So when Biogen looked at the data that they had available from the initial cases of natalizumab-associated PML, one of the risks that they identified was the increased risk of the development of PML in those individuals that had previously received immunosuppressive therapy. And it really didn’t seem to matter which immunosuppressive therapy it was, it was any immunosuppressive therapy. However, it may be different with the different immunotherapies, it’s simply that the numbers weren’t large enough for one to say that this was particularly associated with azathioprine. People in Europe like to use azathioprine often very early in the course of the disease, so they were seeing a bit more PML than we had seen in the United States at least initially. And it wouldn’t surprise me if there aren’t certain immunosuppressive agents that increase the risk significantly compared to others, but we simply don’t have that data. And what is known is that it really doesn’t matter, any of them can do that.

MSDF

Without really having a firm understanding of the pathogenesis of PML – you know the risks but maybe not exactly why it’s occurring – how do you come up with a framework for mitigating risk; is it purely empiric?

Dr. Berger

That’s an excellent question. So it turns out that this was a back-of-the-textbook disease; this was the disease that occurred very, very rarely. Between 1958 and 1984 in a review published by Ben Brooks and Deward Walker, there were only 230 cases that they were able to come up with; 1958, of course, is when the disease was first described. So this was a very, very rare disease until the AIDS pandemic where people developed some interest in it, and then it really became interesting when we saw it with natalizumab. And there’s been more resources put into the study of this disease since then, so that we do have a better understanding of the pathogenesis. But in identifying these risks, we’ve worked backwards; you know, we say, alright, what does natalizumab do? So why is it that we see this increased risk?

So in getting back to your question, we know that immunosurveilling the brain is important; so if you have a drug that prevents appropriate immunosurveillance of the central nervosus system, it should not surprise you that the risk of PML is increased. And we do think that the alpha-4 beta-1 integrin inhibition that occurs preventing the entry of JC virus-specific cytotoxic T lymphocytes into the brain is in a large measure – but not completely – contributing to the development of PML. We also know other things. For instance, the virus that we are likely infected with – and the infection occurs very early in our lives; seroepidemiologic studies indicate that most individuals that are infected are infected before the age of 20 – that that virus is a virus that is ubiquitous but incapable of growing effectively in glial tissues; it is a virus found in urine and found in the urinary tract, it’s found in kidney and renal pelvis and bladder, and it’s found in high concentrations in some people’s urine. That virus will not grow in the brain. So something has to happen to the virus.

Does natalizumab change that in some way? Well, we think it does. We think it does that by causing the release of immature B cells; these immature B cells can harbor JC virus, and that virus as these B cells mature there is an upregulation of transcriptional factors that transactivate the virus, it is occurring in a milieu that may uniquely predispose to a genetic rearrangement of the virus enabling it to become a form of the virus referred to as a prototype strain or a neurotropic strain that can grow in the brain. So we think that there are at least two very large barriers that prevent PML that are affected by natalizumab; there may be others. And as we investigate this disease further, our understanding may improve and these explanations I’m telling you will likely be expanded. And, in fact, it may be that some of the thoughts that we have are wrong, because the story with the B cells is actually somewhat hypothetical; there’s some preliminary evidence supportive of it, and that’s why I tell people that I’m fond of Ralph Waldo Emerson’s comment, that consistency is the hobgoblin of small minds. If I stand before you a year from today and tell you something different, it’s only because we’ve learned more about it.

MSDF

So how do you mitigate risk and how do you get the point across to patients to let them make informed decisions with you?

Dr. Berger

So this is difficult, but we lay the facts out to them. And the facts are that there is this risk of PML, the risk in individuals that are JC virus antibody-negative are very small, the product label puts the risk at less than 1 in a thousand; the belief is that it’s significantly less than that. The fact is that we do see individuals who are JC virus antibody-negative months before the development of PML – it’s rare but it occurs – and there have been studies, including my own, that have indicated that the antibody study doesn’t necessarily mean you’ve never been infected by the virus. So one shouldn’t conflate JC virus antibody negativity with never having been infected, but it is a very good marker for the development of PML, and it is one that needs to be monitored carefully at six month intervals.

So we lay out to the patients that if you’re antibody-negative your risk is infinitesimal and an acceptable risk, and that we monitor you carefully. The second is this is a disease that can be life-threatening, and if not life-threatening certainly severely debilitating – multiple sclerosis I’m talking about – and there are people that have very aggressive disease and will accept the risk of developing PML, knowing that the risk may be 1 in 100, but their risk of developing something that was going to leave them wheelchair-bound and totally disabled is very, very high, and they say I’d rather take the risk of the development of PML.

So we do know what the numbers are. There’s a table that’s been published and gets revised periodically that puts into it JC virus antibody positivity, duration of therapy broken up into 24-month epochs, and prior immunosuppressive use. So we know what the risks are; the highest are in individuals that are treated more than 24 months with the drug, are JC virus antibody-positive, and had previously received immunosuppressive therapies.

MSDF

What about monitoring for signs and symptoms of PML if someone does choose to go on some of these drugs?

Dr. Berger

Yes, so that’s very, very important. And we do have patients that even in the face of JC virus antibody positivity, we and the patient elect to continue them on the drug. And patients on natalizumab need to be monitored very carefully for the development of PML, and that is a combination of both clinical screening – there is a TOUCH program that queries for the development of symptoms that may be concordant with PML – unfortunately, you also see symptoms of that nature develop in MS patients, as well, so it’s sometimes difficult to tell whether it’s MS or PML – and at that point in time you definitely want to survey them with an MRI. And, in fact, many of us do MRIs at regular intervals in patients on Tysabri attempting to identify the disease – PML – when it is asymptomatic. And those people seem to do best; the prognosis both in terms of disability and in terms of survival is better when you pick the disease up while they’re still asymptomatic, and they have what one would refer to as radiographically isolated PML.

So it’s a combination of vigilance, asking the right questions, performing your physical examination, and obtaining period MRIs, and in those that are JC virus antibody-negative – or even the antibody-positive – repeating that study periodically. And the reason I say that repeating it periodically even in the positive patients is because what’s been demonstrated is that the higher your antibody titer, the greater the risk of developing PML. So there’s a threshold now that’s been identified and individuals above that range have a significantly higher risk of developing PML than individuals who are seropositive but below that level.

MSDF

And just to clarify; the TOUCH program is the Tysabri Outreach Unified Commitment to Health? This is what you’re referring to in terms of monitoring for signs and symptoms of PML?

Dr. Berger

That is correct. That is the risk mitigation strategy that is FDA-approved and that Biogen has implemented in an effort to decrease the likelihood of PML developing.

MSDF

Very good, thank you.

Dr. Berger

My pleasure.

[transition music]

Thank you for listening to Episode Thirty-Eight of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is vice president of scientific operations.

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

 [outro music]

[intro music]

Host – Dan Keller

Hello, and welcome to Episode Thirty-Seven of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.

This week’s podcast features an interview with Jeanne Loring, who works with human induced pluripotent stem cells in a mouse model of MS. But to begin, we’d like to tell you about one of the most useful features of the MS Discovery Forum.

Each week somewhere between 30 and 110 papers related to multiple sclerosis are published in the scientific literature. At MSDF, we endeavor to list them all, publishing links to a curated set of each week’s new papers every Friday at msdiscovery.org/papers.

The first step in curating this list is an automated PubMed query that pulls all papers containing the terms multiple sclerosis, myelin, optic neuritis, acute disseminated encephalomyelitis, neuromyelitis optica, transverse myelitis, experimental autoimmune encephalomyelitis, cuprizone, neurodegeneration, microglia, and several related terms. This query returns many false positives. MSDF editors read all the titles and most of the abstracts and make judgments about which papers are directly relevant to MS or related disorders. Last week, for example, the query returned 139 papers and, in our judgment, only 58 of them – 42% – were truly MS-related. Some weeks the proportion is even lower than that.

The query terms neurodegeneration, myelin, and microglia are responsible for most of the false positives. Neurodegeneration, in particular, returns many references related to other neurodegenerative disorders, such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, stroke, and hypoxia, to name a few. Editorial judgments on which articles are relevant are often subjective, and we frequently struggle with those decisions. It’s easy to decide relevance when an article actually mentions multiple sclerosis. It’s harder when it mentions only myelin or only Th17 cells. If you think we’ve missed an important MS-related article—or if you think we’ve included an irrelevant article—I hope you’ll let us know by emailing us at editor@msdiscovery.org. And we’re open to suggestions on how to adjust our PubMed query to decrease false positives and false negatives.

Once we’ve chosen which of the articles to include in the week’s list, we select between two and four of them as Editors’ Picks. Those are the week’s articles that seem to us to be the most important or interesting or intriguing. Once again, we invite readers to take issue with our choices. We’d love to hear about important articles that we have not designated Editors’ Picks or, on the contrary, Editors’ Picks that don’t deserve the honor.

[transition music]

Now to the interview. Dr. Jeanne Loring is Professor of Developmental Neurobiology and Director of the Center for Regenerative Medicine at the Scripps Research Institute in San Diego. She and her collaborators have been testing human neural precursor cells derived from embryonic stem cells in a mouse model of MS. The cells are injected into the spinal cords of immunocompetent mice with a model of MS induced by a neurotropic hepatitis virus. The cells are rejected within a week, but in that time they suppress the immune system and induce remyelination.

Interviewer – Dan Keller

In terms of how you came upon your most recent finding about human pluripotent stem cells in the mouse model of MS, could you give me a little bit of the back story?

Interviewee – Jeanne Loring

Oh yeah, sure. It was really interesting. So Tom Lane and I set out to try to develop a stem cell therapy for MS using human cells. So as a control experiment, we took human pluripotent stem cells, in this case embryonic stem cells, and turned them into neural precursors; differentiated them just a little bit. And then we transplanted them into Tom’s mouse model of MS. These mice were not immunosuppressed, and so we expected the cells to be rejected. And this was just our first experiment. But the results were not what we expected. After the cells were rejected, the mice started getting better, and their clinical scores improved. And then after several months, these mice were almost indistinguishable from normal mice.

The first thing we thought was that we’d gotten the cages mixed up, and we were looking at something different. But we’ve repeated the experiment now more than a hundred times, and about 75% of the time we get the same result. So what this tells us is that these cells that we put into the animals are having some effect during the seven days that they exist in the animals that leads to both immunosuppression and remyelination and a clinical improvement which is quite remarkable.

MSDF

When you say 75% of the time, does that mean you get almost no effect 25 % of the time? Or does it mean that 75% or the mice? Because that would say whether you’re making your stem cells right or not.

Dr. Loring

It’s 75% of the mice.

MSDF

How do you explain it at this point, or where do you go from here to find a way to explain it?

Dr. Loring

So once we’d realized that we had a phenomenon that was repeatable, we realized that there was something special about these cells. And we tested other cell types, like the pluripotent stem cells that they were derived from, and human fibroblasts, and discovered that neither one of those was effective. And since then we’ve also tried other ways of making neural precursor cells, and those cells aren’t effective either. So it’s something extremely special about the cells that we used in these experiments, which is very lucky when you think about it.

So we’ve now, both Tom and I – even though we’re not in the same place – we’ve set out to try to find out what it is about these cells that gives them these properties. Our first sort of cut on this – our hypothesis – is that the cells are secreting something that has a lasting effect. Our sort of big picture idea is that there are probably more than one protein or glycoprotein being secreted. And together they suppress the immune system so they act on the inflammatory response so that they increase the number of regulatory T cells that are produced and decrease the other T cell types. And they induce remyelination.

So Tom is now working on trying to identify what factors these cells make that are inducing the T regulatory cells. And on my side, we’re trying to identify what it is that makes them remyelinate.

MSDF

When you make these cells, how do you know you got a good batch? Can you characterize them? Are there biomarkers, and you can say, “We did it right this time?”

Dr. Loring

Yes. In fact, that turns out to be really important because we did it wrong a few times. And we have a gene expression signature. It’s essentially diagnostic assay for this particular cell type. We’ve boiled it down to a set of qRT-PCR markers. And, because we have collaborators in Australia, we had to be able to transfer this quality control assay to them. So far it seems like those markers, I think it’s a group of 10 or 12 markers, seem to be predictive of the cells’ working in the animals.

MSDF

And just to clarify, that’s real time quantitative polymerase chain reaction? How are you going about characterizing what they’re doing? I mean, are you doing cytokine measurements or you’re looking at cells that get produced in the mice?

Dr. Loring

Tom is really handling the cells that get produced in the mouse. He’s doing the T cell analysis. What we’re doing, we developed an in vitro cell culture method to look for the effect of these cells on maturing oligodendroglia in culture. And we found that something secreted by these cells which shows up in their culture medium actually induces maturation of oligos – of OPCs – in vitro. I guess that’s another result that we didn’t expect to be quite so clear. So that shows that there’s something that is secreted by the cells. I mean, that’s the most likely idea. And on Tom’s side, he’s shown that the conditioned medium from the cells induces T-reg generation. And on our side, we’ve shown that conditioned medium from the cells induces oligo maturation.

So now we’re trying to figure out what it is in that conditioned medium because now we think we can do a cell-free therapy for MS if we can identify what the factors are. It would be much simpler for us to do even a protein therapy for MS than it is to do a cell therapy. So both sides are taking sort of a candidate gene approach in which we’re identifying the proteins that are most highly specifically expressed in the cells that work in the mice. We have a list of those proteins, and we’ve sort of snatched a few candidates out of that group, and we’re testing to see whether each one of those proteins in purified form has the same effect as the conditioned medium.

The other approach, which is more tedious but more likely to actually tell us what’s going on is for us to fractionate the medium into different sized proteins and then test each one of those fractions. We’re in the process of doing that right now.

MSDF

But it sounds like these cells are pluripotent. Not pluripotent in the normal sense of a stem cell leading to different lineages, but they have a couple of effects. One is the immunomodulatory, the other is regenerating oligodendrocytes. Do you think it really requires the gamish of proteins? If you fractionate them, will you possibly lose the signal? And that’s a big matrix to put back together again.

Dr. Loring

Yes, it is. And obviously, if we get no signal from our fractions, we’ll put our fractions back together again and try to find out whether – there are only three fractions, really, right now. So we’ll try different combinations of these fractions to try to find out if we can reproduce the effect. The effect is quite robust. We essentially get no maturation in medium conditioned by other cell types, but we get very strong maturation when we use conditioned medium from this particular neural precursor cell.

MSDF

If you only have three fractions now, is it because you just have chosen not to fractionate it even more until you know what’s going on?

Dr. Loring

Yes, we’re trying to hone in on it. So we don’t want too many different things to look at right away. I’m hoping that we find that only one of those fractions works, and that we can discover everything is within that fraction, but I really can’t predict what’s going to happen.

MSDF

It sounds like the approach would be to put everything in except one each time as opposed to keep adding back. You’ve got to find the one critical one missing that makes the thing not work.

Dr. Loring

Yes, and eventually we will do that with specific antibodies, but right now that is, since we don’t really have our candidates narrowed down enough, that isn’t a viable approach. But you’re absolutely right. We want to find out if that’s missing, whatever the things that are that are missing. And I’m hoping it’s not so complex that it’s five or six or seven proteins, because that’ll make it much harder for us.

MSDF

How do characterize the condition of the mice?

Dr. Loring

So that’s Tom’s area of expertise. It’s essentially an observation of the mice over time. We have a movie which I can show you, but I can’t actually do it in a recording. It’s quite obvious when the mice – they’re blind scored so the person who looks at the mice and sees how well they’re walking around doesn’t know whether they’re controls or experimentals. If you just see the movies that are selected at particular times after the cells have been transplanted, it’s quite dramatic. They have a much better clinical score. Essentially, they’re almost normal after six months.

MSDF

And how are you sure that the cells you injected into the spinal cord are gone, that they’ve been rejected completely?

Dr. Loring

That’s a good question. We used a method for live imaging of cells in which we use luciferase to label the cells. And then we used an instrument which allows us to image the cells in mice – in living mice – over time. So we did this in individual mice and saw that they disappeared over time. And after eight days we couldn’t detect them anymore. That doesn’t mean there isn’t one or two left because the resolution isn’t that high. We will go back eventually and look through sections of the spinal cords and see whether we can detect any. The other thing we can do is (skip 13:37) a human-specific markers. So we can just take a section of the spinal cord and find out if there’s any human cells in it at all, or any human genes in it at all. But we haven’t done that yet.

MSDF

Do the cells have to be gone? Have you tried injecting a second time?

Dr. Loring

No, we haven’t. We don’t know. We really don’t know. It would be very interesting if it reversed the effects. Then we’d really have a problem to solve.

MSDF

What else is there important to add or that we’ve missed that’s important to this kind of research?

Dr. Loring

So our dream is that we will identify a group of proteins and the concentration of those proteins necessary to have these two effects in this mouse model. And then we will do some biological engineering. We’ll be putting the cells into these little spheres and matrix that allows slow release of these proteins or controlled release of these proteins. And then, instead of putting cells in, we’ll put these beads in. And I don’t know whether that would end up being the final product or not, but there are lots of ways to deliver proteins, and this one I find rather attractive because it doesn’t require pumps or syringes. And I think that’s certainly the direction we’re going to try to go in. And so Tom Lane and I have just gotten an NIH grant for five years of funding, which seems like a very long time to me. So in five years we will have discovered the best way to deliver these things. We’ll discover what they are and the best way to deliver them. Tom has put conditioned medium into the mice, and it also works.

MSDF

Because I was going to ask, had you encapsulated the cells just to see that the supernatant does it without cell contact?

Dr. Loring

It turns out that the conditioned medium itself, you inject that into spinal cord, it’s not as dramatic an effect, but you have a clear clinical improvement.

MSDF

Have you tried injecting it either IV or intraperitoneally?

Dr. Loring

Yes. Well, we didn’t inject the conditioned medium. We did try injecting the cells, and they pretty much stayed where we injected them. These cells, unlike mesenchymal stem cells, they aren’t very migratory. So they don’t really have the receptors that cause them to move to areas of inflammation like CXCR4, for example; they don’t express that on their surfaces. So that does not seem to be a good delivery method for these cells. They don’t go anywhere.

MSDF

I was also thinking that if something they secrete is important, whether it circulates. Maybe they’re not making enough concentration if you inject them outside of the central nervous system, but it seems like you’re going to be faced with a little cumbersome problem in a clinical situation years and years ahead from now if you have to keep injecting proteins into the spinal cord as opposed to more peripheral.

Dr. Loring

I agree. And the solution to that is generally to look for peripheral effects and then try to suppress those when you do a therapy like this. That’s a long time, and we could certainly imagine how we would do it. But we need to know what those proteins are before we can decide on whether we expect them to have effects peripherally or not. But I agree with you; delivering them intravenously would be far easier.

MSDF

I know you have a lot of work ahead of you now with this, but is there another animal model of MS – or even another mouse model of MS – where you can see if it works even in a mouse model different from this one?

Dr. Loring

Yes, we’re actively pursuing that with our collaborators in Australia. And it’s interesting because they’ve gotten some positive preliminary results using the EAE model, but the approach to the EAE model I’ve realized is quite different. Generally, what people do is they provide the therapy at the time that the pathology is developing, and they try to prevent it, which is a really different idea than what we had using the mice that are already paralyzed. So they have found that if you can deliver the cells at least close to the spinal cord, then you can see some effects. The problem is that in Australia, and this is one of those technical things we had not anticipated, they don’t have permission to inject cells into the spinal cord. So they have to go through their animal rights people or their animal protection groups and try to get permission to do so. So with Craig Walsh at UC Irvine we have started doing parallel experiments with the EAE model. I’m not necessarily sure that it’s going to have similar effects. I mean, I really don’t know.

MSDF

Can you describe how these mice in your experiments were made to have MS?

Dr. Loring

Yes, they were given a virus, a neurotropic virus, which kills off the oligodendroglia. They become demyelinated, and there is a secondary inflammatory response. So the mice are actually paralyzed in their hind quarters at least by the time we put the cells in. They have to be fed by hand. So this is not a trivial thing to do. But we’re trying to reproduce the effects during the progressive form of MS, for example, or during an attack of MS. So we’re trying to repair the mice or cure the mice that are in a condition which would be similar to the worst case scenario for people with MS.

MSDF

Do you think this may also have effects not only on the myelin, but also on damaged neurons?

Dr. Loring

We don’t know, because the mice haven’t really had enough time to get a lot of neuronal damage, but that’s a very good question. We don’t know yet.

MSDF

I appreciate it. Thank you.

Dr. Loring

You’re welcome. It was a pleasure.

[transition music]

Thank you for listening to Episode Thirty-Seven of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is vice president of scientific operations.

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

[outro music]

[intro music]

Dan Keller: Hello, and welcome to Episode Thirty-six of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.

This week’s podcast features an extended interview with Jenny Ting, an immunologist who studies the inflammasome, a multi-protein oligomer that’s part of the innate immune system. But to begin, we’d like to tell you something about why we started the MS Discovery Forum.

MSDF, located at www.msdiscovery.org, is an online portal providing news and information about research in MS. We offer a unique combination of news and background articles written by professional science journalists, viewpoints from thought leaders and subject matter experts, and technical resources that enable sharing and analysis of information and open discussion among MS stakeholders in academia, industry, and the clinic. Membership in MSDF is free, and all content on the site is provided on an open-access basis to the entire MS community.

MSDF stands apart for its comprehensive and independent coverage of MS research. Readers can depend on MSDF to report and verify, not merely re-run press releases. MSDF’s overarching goal is to accelerate progress toward clinically useful advances.

We launched MSDF in April 2012 with the aim of filling a knowledge gap in MS research. The plan was to promote collaboration among scientists who are separated by specialized skill sets, institutional boundaries, and geography. It’s well known that these individuals attend different meetings and read different journals. And while it’s common knowledge that scientific breakthroughs and medical advances most typically result from cross fertilization of ideas, in today’s world scientists still do not easily share ideas and collaborate on solutions. We wanted to change that, and to bring thoughts, knowledge and ideas out from the lab into the open to enlighten and inform all stakeholders in the effort to cure MS, including health care providers and people affected by MS.

To that end, we employ the highest standards for independent journalistic reporting, including the use of multiple viewpoints to give a full picture of a finding’s impact. We aim to make scientific findings accessible to everyone, from busy clinicians to cutting-edge researchers to people with MS and their loved ones. We avoid short-cuts, such as the use of jargon, that get in the way of comprehensibility. We highlight the potential clinical impact of the research we cover, even when we’re covering basic research that may be years from direct clinical relevance. And we seek innovative ways to communicate important information to our audience.

[transition music]

Now to the interview. Dr. Jenny Ting is Professor of Microbiology in the Institute for Global Health & Infectious Diseases at the University of North Carolina at Chapel Hill School of Medicine. In addition to MS, Dr. Ting’s research interests include the role of the immune system in infection, inflammation, and cancer. Science Journalist Carol Morton caught up with Dr. Ting at a recent Keystone meeting.

Carol Morton: I appreciate your taking time out to talk to MS Discovery Forum. So we’re at the Keystone meeting on Neuroinflammation in Taos, New Mexico, and you gave a very interesting talk today.

Jenny Ting: Thank you.

Morton: So can you tell us what you’re talking about when you’re talking about the inflammasome and the particular proteins that you’ve been looking at.

Ting: The groups of proteins that we work on are cytokines, and cytokines are made by immune cells. And they have a tremendous impact on inflammatory responses. As you know, in MS there is a big immune component, so these cytokines will influence it. And in most cases cytokines activate the immune system. One of the key cytokines that we’ve studied is called IL-1, interleukin-1 beta; this is the one, for example, that causes fever, inflammation, and so forth. So it’s called interleukin-1 because it was the first one discovered, and it turns out it’s probably one of the most important ones.

So because it’s a master cytokine, and once it goes it kicks off all the other cytokines, so there’s a cascade that goes on. So it could activate other cells to make other cytokines, so it’s like a vicious cycle. Obviously, this becomes a pretty important target to think about. The process that causes this cytokine to be produced is a very big molecule that’s comprised of different proteins. And these different proteins, they are, together, called the inflammasome for inflammation large complex because “some” means large complex. Inflam- is inflammation, as in inflammasome. It’s the name given by Jürg Tschopp.

And so this process where you have this big complex, and as a result you get the cytokine called interleukin-1 beta, what happens is that interleukin-1 beta has now been implicated in so many diseases including arthritis, very rare diseases that causes a lot of inflammatory responses. It’s involved in skin allergies. It’s involved in colitis, you name it, and it’s involved in smoke-induced chronic obstructive pulmonary disease, COPD, that we see advertised on TV. So all of these have this component of this molecule.

Morton: So anything that releases IL-1 beta, inside the cell there’s a cluster of proteins that have to come together to make it.

Ting: Right.

Morton: And then it gets secreted and does its job.

Ting: Yes. And as we learned today, and actually it’s been published, but may be new to some of the audience, is that this whole complex can also be excreted in some ways into the cell, you know, pushed outside of cells so it can go from perhaps one cell to the other. So we have previously found that this can be a complex that’s membrane bound, and that’s called an exosome. So it’s both just like a minicell that goes from one cell to the next and make the next cell inflammatory as well. The speaker today showed that, in addition to that, it can also go out as a complex, perhaps naked. It seems like they are not really membrane bound, so that’s a different form. So it could be different forms that goes out from one cell to the next causing inflammasomal activation in the next cell and therefore perpetuates this IL-1 process.

Obviously, in normal hosts there must be a way to turn off this process, otherwise we would be, you know, a little ball of pus sitting on a chair. So obviously these don’t go on forever. The problem with chronic inflammatory diseases is many of these things, they don’t go on probably all the time, but they do increase. So what we did is really look at mice lacking genes that can make these proteins. This complex is usually comprised of at least three components; you knock out one and you can’t make IL-1 anymore. Actually, I should say five components. So we did that, and what we found was that if you take this out, the models of MS suggests the well-known mouse model, EAE, and another model that we’ve been really pushing, although it was initially worked on in the late 1960s and early 70s, this model of neurotoxicant-induced demyelination. In both of those models this process of inflammasome/IL-1 turned out to be bad.

So if you remove this process, the disease is much more attenuated. So that’s one of the really interesting parts about what we had found is that potentially this could be a target. And the good thing is that there is certainly some companies that have successfully made anti-IL-1s. So there is an IL-1 receptor antagonist that inhibits this process. There is an antibody against IL-1 that will inhibit this process. So certainly there are therapies, if this is true, that this is part of the MS problem that this could be used as a therapy.

The other thing we have found, which I didn’t get a chance to talk about, is that we did look at the remyelination phase and found out that, for example, IL-18 is not very good for remyelination. Of course, remyelination is what everybody would like to have, is a reparative process. And so one possibility is, can we block the IL-18 pathway, and can we get better remyelination processes. So those are some of the thoughts that we have.

Morton: So have you examined a number of the ILs from 1 to 18 or…?

Ting: No, because 18 is the product. So this inflammasome actually has many different targets. One of them is IL-1 beta; that’s the key one. Another one is IL-18. So we went from there to look at what’s downstream of the inflammasome and found out that IL-18 actually has a role both in making MS disease models worse and in reducing the extent of remyelination. So it doesn’t look like it’s a great protein to have around. So the question is can we try to inhibit this molecule.

Morton: Just to make sure that I’m clear on that: the inflammasome is a cluster of proteins that come together in an immune cell, like a T-cell, or a…

Ting: Usually it’s a macrophage or a microglia or an astroglia.

Morton: A macrophage or a microglia. And then that makes the IL…

Ting: So what you have is – I don’t know if the audience might be familiar with the coagulation pathway where you have one protein that has to be cleaved into a smaller protein. Then this protein B goes and cleaves a second protein from a bigger form to a smaller form. And the smaller form, in every case, is the mature protein that has activity. The bigger protein is the inactive form that doesn’t do anything. So this exactly the same. Pro-IL-1 has to be cleaved into IL-1. Pro-IL-18 has to be cleaved into IL-18. And what that cleavage process is this inflammasome complex producing an enzyme that will cleave these proteins.

Morton: So the inflammasome is like Edward Scissorhands running around cutting proteins making them active.

Ting: Yes, that’s a great analysis. So it’s just exactly like that. The inflammasome produces this – like you said – Edward Scissorhand that then this guy can go and prune the roses and prune the bushes, and they’re different, and they have different functions.

Morton: And it’s the starting block for the activity of the IL-1 and IL-18.

Ting: Right, so the bushes are like – if the roses are the IL-1, you can decorate it; you can give it to somebody; you can make it into a bouquet. So that’s the kind of idea. And then if you have a bush, you know, you can potentially do other things with it. Or if he’s cutting some edible plants you can use that for cooking. So that’s the whole idea. Whatever you produce has different effects. And it turns out IL-18, in our hands, looked like it’s not a good molecule. We have previously found that a cytokine called TNF, which has different roles depending on what it binds. So if it binds to TNF receptor 1, then it’s not so good. If it binds to TNF receptor 2, it actually enhances remyelination, so again, something you want.

And there’s recent talks and there are small molecules where people tried to activate the TNF receptor 2 pathway, and they found that that really enhances the remyelination process. It’s kind of really neat; if you can dissect these pathways well enough, then you might be able to use drugs to target MS.

Morton: So what are the next questions that you’re asking? Where are you going from here?

Ting: So we have a number of directions. Certainly, like I say, I raised the concept of IL-18; so can we target that molecule? In our own lab we’re also looking at several other pathways. So we have found a pathway that’s really important for cell-cell interaction that’s important for MS activation. And the molecules are called plexins and semaphorins. And this is a pair of proteins that seems to activate the immune system especially during MS. So we’ve done that in disease models, and we actually produce a blocker of that pathway. And we have treated mice, and they look much better. We showed that when they’re going through relapse, we can actually prevent them from coming back with a relapse.

So, very similar to some other MS drugs that are on the market, we’d like to think about this as additional possibilities. So those are some of the things that we’re doing.

Morton: What cells are these on?

Ting: These are T-cells and dendritic cells so they’re…

Morton: They’re talking to each other.

Ting: Yes, exactly, they’re talking to each other. And in an MS situation they talk to each other, they activate T-cells, which destroys the myelin. So if you can block that interaction, many of the drugs that are used for MS actually are targeting exactly that interaction pathway. For example, Tysabri is one that’s not so much dendritic cells and T-cells, but it reduces T-cell migration through the vasculature into the blood brain barrier. So that’s one of them where they block T-cell activation. So we are trying to block T-cell activation as well, but at the face of these two cell types.

Morton: If the inflammasomes, if they were superheroes or characters in an Oscar-winning movie, what would their personalities be, do you think?

Ting: I think they would be very powerful because they impact a lot of disease processes, yet they have very strong roles so that, when they’re used properly, they can defend against all sorts of stuff. Whey they’re used improperly, they can really cause a lot harm. So if they’re a superhero, people always say Batman has a dark side, right, a really dark side and a really good side. Maybe that’s what they are.

Morton: That’s a good analogy.

Ting: They’re not like Superman because Superman seems like all good.

[transition music]

Keller: Thank you for listening to Episode Thirty-Six of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is vice president of scientific operations.

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

[outro music]

[intro music]

Hello, and welcome to Episode Thirty-Five of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.

This week’s podcast features an interview with Daniel Reich, an expert in MS neuroradiology. But to begin, here’s a brief summary of some of the latest developments on the MS Discovery Forum at msdiscovery.org.

Every week somewhere between 30 and 100 scientific papers related to MS are published in the peer-reviewed literature. And every Friday MSDF lists them all. You can find this week’s list, as well as three years’ worth of past lists by clicking on the Papers tab at the top of every MSDF page. In addition to listing the new papers, we also have a section containing classic papers in the field, along with commentary about what makes them classic. We’d love it if you’d like to suggest a classic paper we haven’t yet listed, and we’d love it even more if you’d like to contribute commentary. Please send your suggestions to editor at msdiscovery.org.

In addition to detailed original reports on new research, MSDF also curates MS-related news from around the Internet in a series of news briefs we call Research Roundups. In our latest Research Roundup, we reported on a second case of progressive multifocal leukoencephalopathy in a patient taking fingolimod. We mentioned a new trial of mesenchymal stem cells that will soon begin recruiting people in Canada with relapsing or progressive MS. And we pointed out that while scientific research was a favorite choice of America’s 50 biggest philanthropists last year, no neurological disease benefitted directly from the $1.6 billion they contributed. If you happen to have one of those folks on speed dial, we hope you’ll put in a good word for MS research. You can find our Research Roundups by clicking on News and Future Directions and then on News Briefs.

If you enjoy this podcast and find MSDF helpful, please consider supporting us with a donation, even if you’re not a billionaire. MSDF is run by a small team of reporters and editors. We are devoted to bridging the gaps between scientific disciplines to speed the flow of information from the lab bench to the bedside. Our ultimate goal is to facilitate the discovery of a cure. We believe one of the best ways to do that is to bring independent, research-focused news to a professional audience on a platform that fosters discussions and discourse. Help keep us going by visiting our website and clicking on the green “Support MSDF” button next to the “Research Resources” tab on the top right of our screen.

[transition music]

Now to the interview. Dr. Daniel Reich directs the Translational Neuroradiology Unit in the National Institute of Neurological Disorders and Stroke, part of NIH. In his practice as a neuroradiologist, he cares for patients with multiple sclerosis and other neurological diseases, and he also leads several clinical studies. Research in Dr. Reich’s lab focuses on the use of advanced MRI techniques to understand the sources of disability in multiple sclerosis and on ways of adapting those techniques for use in research trials and patient care. Dr. Reich is also a member of MSDF’s scientific advisory board. Science Journalist Carol Morton caught up with Dr. Reich at the recent Keystone meeting on Neuroinflammation in Diseases of the Central Nervous System in Taos, New Mexico.

Interviewer – Carol Morton

Can you tell us the value of MRI in multiple sclerosis?

Interviewee – Daniel Reich

The way I see it, MRI has tremendous value in multiple sclerosis in three major ways. One is in the clinic, one is in clinical trials, and the third is really for understanding the biology of the disease; it’s an incredibly powerful tool for that. And in my own evolution as a clinician and researcher in multiple sclerosis, I’ve really moved my thinking a lot from kind of using MRI diagnostically or thinking about how we might develop markers of the disease to look at in clinical trials to really the third part, which is trying to understand the disease using the MRI, or sometimes as I call it, the MRIcroscope.

Because really it is, in a way, a scientific tool to look at aspects of the disease that we can’t access either because we can’t study the brain tissue or the spinal cord tissue directly, and because it’s really much more sensitive than doing clinical evaluations in neurology. So one of the interesting things that came out from early MRI studies in the 1990s, many of them done at the NIH long before I got there where they started doing MRIs every month on people even before the era of disease-modifying therapy, was that new plaques that appeared in the brain occurred roughly ten times more frequently than new symptoms appeared in the form of relapses.

MSDF

Ten times?

Dr. Reich

Ten times, or maybe even more. But that was with the sensitivity of the techniques that were available then, that was the number that was found. What that’s telling you, of course, is that there’s a lot of subclinical disease activity that’s going on that we can completely miss if we are just doing examinations or asking patients to report their symptoms.

MSDF

Have there been eras of MRI use in MS and where are we now with it? And that could be in clinical trials and biology.

Dr. Reich

We’ve made a lot of progress, I think, in all three areas. The MRI is absolutely the most important paraclinical tool for making the diagnosis of MS. And since the newest generation of diagnostic criteria were established, the McDonald Criteria, MRI has really formed the centerpiece of those. So in somebody who is having symptoms that may be due to multiple sclerosis, the MRI is absolutely the most important test that can be done. And, in fact, it’s now evolved to the point where the diagnosis can be made based on a single MRI at one time in many cases in somebody who comes in with the appropriate clinical symptoms.

MSDF

A new challenge confronts the whole MS community in developing therapies and monitoring outcomes of interventions for progressive MS.

Dr. Reich

Yes. So how might MRI play a role in assessing therapies for progressive MS? That is a huge challenge. It’s a challenge I would say the majority of my colleagues in the imaging field in MS are working on; what can you measure with MRI that might be the equivalent of new plaque development for the progressive MS question? And it’s, in my view, quite unresolved. The most studied markers that have behind them the weight of evidence to date is brain volume changes – how much brain is there – which can be assessed with MRI and is being done routinely in clinical trials now. I think how exactly that’s being done, which parts of the brain to look at – grey matter, white matter, specific portions of the brain like the thalamus – remains an open question.

What quantitative analysis tools should you use to make the measurements from the images? How you set up the scanner? All of this is still being worked out. That idea of measuring brain volume and seeing whether therapies may slow the rate of brain volume loss appears to be relatively promising. But even with that, proof of concept early trials to see whether a therapy might work are still much larger and much longer than the proof of concept trials that work for assessing new therapies to reduce the number of plaques.

MSDF

By how much longer?

Dr. Reich

They usually are two years or so at the minimum and they would involve on the order of 100 to 150 patients. Contrast that to four to six months with 10 to 15 patients and you can see how many more therapies can be tested with the shorter, smaller approach. So, in fact, in our lab, one of the things we’ve been thinking about a lot is how we may shorten that. And in the context of progressive multiple sclerosis, I think that’s not clear how to do. However, a lot of the biological processes that are occurring in progressive multiple sclerosis, there’s now a lot of evidence that they also occur very early in the disease, perhaps even before somebody has their first symptoms. So these brain atrophy processes, I think that’s been quite well established.

But you can also ask the question of whether brain tissue repair. Parts of the brain that have been demyelinated that requires remyelination that occurs early in the disease and it may be relevant for progressive phases of the disease as well, or for people who have primary progressive MS. And so we’ve been thinking a lot about how to look at these early plaques that develop early in the disease and use imaging of those plaques to see how they repair in order to test new therapies coming down the block that may promote remyelination or protect brain tissue that’s undergoing inflammation and demyelination from more extensive destruction. And we think, based on the some of the work we’ve done that is going to be published next week, that we can design trials that are, again, very short – six months or so with 10 to 20 patients, 15 to 20 patients – that may be able to assess that. And, of course, we’ll need to understand whether success in such a trial would predict whether that therapy would work in larger trials of progressive MS.

MSDF

Are there other challenges with MRI and related to multiple sclerosis?

Dr. Reich

Sure. From the point of view of doing clinical trials that are generalizable to large groups of patients that are able to be implemented at multiple sites, we need to understand how to standardize our techniques better. I’ve been involved with an effort recently to develop a group of cooperating investigators in North America similar to our older, more venerable brothers and sisters in Europe who have been working together on imaging for 20 years or so in the MAGNIMS Consortium. Our group which is called the North American Imaging in Multiple Sclerosis Cooperative – or NAIMS – is really very interested in trying to understand how we can standardize high-end approaches that may be very effective for testing new therapies that may be useful for assessing tissue or repair. With this consortium, the NAIMS Consortium, we’ve been very interested in developing standardized protocols that could be useful for assessing in a multicenter way, whether new therapies that are designed to repair or protect brain tissue and spinal cord tissue work. So we’ve been working very hard to do that, and we hope that once a study can be done in multiple sites, it can often be done much more efficiently.

From a diagnostic point of view, the types of MRIs that are done at all different centers may be equally good for just assessing, for example, whether plaques are present in the brain of somebody who is being worked-up for multiple sclerosis. But if you have to take the next step to quantify that and to submit those results to statistical analysis, then you really need a lot more homogeneity. It’s not actually clear how much homogeneity you need, how much narratization you need, that’s an open question. Does it need to be exactly the same, or does it need to be approximately the same, or really do we need to understand the differences between what is done at one site versus what is done at the other?

The last area in which I think MRI is incredibly valuable and offers something that no other technique really can is the ability to study the spatiotemporal dynamics of the disease. MS is, of course, a disease that affects people young and that they carry with them for their entire life, so it can last 40, 50, 60, 70 years in some cases. And I think we all know that the disease changes a lot during that period, and it changes as people are changing and as they age, and you can’t take pieces of the brain or spinal cord and study it under the microscope. I mentioned already that clinical evaluation is less sensitive than the MRI for picking up these changes, so only with the MRI can you understand how things change and where they’re changing in the brain.

In that context, I think people have been going along one of two pathways for how to use MRI to understand the biology of the disease. On the one hand, people have been using the physics of MRI to build really complicated models of how different types of tissue changes – demyelination, inflammation, atrophy – could affect the pictures we take, and that’s been a very interesting but quite complicated effort and the results have been a little bit hard to interpret. The other approach is to take advantage of the rapidly evolving technical changes in MRI acquisitions to really just learn how to take higher and higher resolution pictures.

And I think that’s the bias that we have in our group, that’s the approach we’re taking where we think that as we begin to hone in on really fine features of structures of the brain, whether it be the cerebral cortex or the spinal cord or the brain stem or the cerebellum, we’ll begin to see things that will help to bridge this divide between what people can do in the lab with really fancy molecular techniques with what they can do in the clinical with MRI. And so that’s really where we’ve been spending a lot of our effort using very powerful MRI machines – 7 Tesla – using very advanced antennas – we call them coils – in MRI to really get high-sensitivity images.

Changing the way we tune the magnet to focus on things that we think are interesting. For example, one of the areas we’ve been studying quite intensively recently is inflammation in the meninges in the coverings of the brain, which we think from the pathological data are quite relevant to the disease. We have a way now that we’ve described of assessing at least some of that inflammation in MS, and we’ve been following up on that. So I think the potential of MRI as a biological tool, even after 30 years of work on it, is really largely untapped.

MSDF

Are there things that the MRI can’t do right now that you really want it to do?

Dr. Reich

Oh, absolutely. You know, MRI is based on the physics of how protons behave in a strong magnetic field and when those protons which are largely in water are aligned when they go into a magnetic field. And we can perturb that alignment, and then it relaxes back into the equilibrium state. And the rates at which that happen depend on where these protons are located, and that’s what allows us to see the tissue. And I go into that because it just illustrates that we’re not looking at T cells and B cells and microglia and axons and oligodendrocytes, we’re looking at the physics of protons in a magnetic field.

I would, of course, love to have a technique that combines the exquisite submillimeter spatial resolution of MRI with specificity for these various cell types or biological processes that are going on. And a lot of people have been working on this, but to date that doesn’t really exist. And part of the reason for that is because the biological processes don’t occur in isolation. Lots of different things happen with inflammation – water moves around – and so it may actually not be possible to do that, but people are still working in that. So that’s a great challenge is to figure out how we could specifically assess inflammation, myelination, axonal health with imaging. But I don’t think that precludes us, again, from using the imaging either to help with the diagnosis, to assess new therapies, or to really observe and build stories about how the biology is working in the disease.

MSDF

What’s happening in the cutting-edge of MS neuroradiology?

Dr. Reich

I think the most exciting development in MRI and multiple sclerosis is the ability to look with greater and greater precision at what’s going on in the brain and spinal cord, and how that changes over time. And that is being made possible by really rapid advances in the technology. I think that will no doubt translate into the ability to better assess the course of an individual person’s disease, whether they’re responding to therapies, either immunomodulatory therapies that current exist or the reparative or protective therapies that will hopefully come online soon. And I think that’s tremendously exciting.

MSDF

Do you also collaborate with people in other specialty areas in the course of your work?

Dr. Reich

Yeah. Personally, I have many collaborations. I have collaborations with pathologists, I have collaborations with immunologists, with clinicians, with virologists, with other imagers. So for my work which really depends on understanding the intersection between the imaging we do and the biology of the disease, those collaborations are critical. Through our NAIMS Cooperative, the imaging group in North America that we’ve recently started, we’re hoping really to develop very powerful interactions among groups that have a lot of expertise in how to do imaging in multiple sclerosis.

So in addition to the standardization work, we’re very much hoping to be able to share techniques that we develop. And we’ve established a platform in which that is happening. We’re also hoping to use this cooperative group to sort of cross-pollinate the various labs to use it as a training forum so that the next generation of people interested in imaging and MS will, number one, get to know each other, but also learn from labs in which they don’t spend all their time. So it has a multipartite mission which hopefully will really drive the field forward.

MSDF

Well, thank you for sharing your thoughts on MRI and MS with MSDF.

Dr. Reich

It’s my pleasure.

[transition music]

Thank you for listening to Episode Thirty-Five of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is vice president of scientific operations.

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

 [outro music]

 [intro music]

Hello, and welcome to Episode Thirty-Four of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.

This week’s podcast features a follow-up interview from last week’s episode with Dr. Pierre-Antoine Gourraud. This week, we interview Dr. Jill Hollenbach about killer immunoglobulin-like receptors – or KIR – and their relationship with human leukocyte antigen and MS. But to begin, here’s a brief summary of some of the latest developments on the MS Discovery Forum at msdiscovery.org.

Take some time to check out our most recent data visualization on our website. Under the research resources tab, you can find a series of interactive data visualizations useful for MS researchers. Our most recent one organizes 142 ongoing clinical trials into an interactive bubble chart. We have another visualization on the natural history of MS symptoms. The interactive bar chart allows you to see the change of various symptom severity in MS over a 30-year period.

If you enjoy this podcast and find MSDF helpful, please consider supporting us with a donation. MSDF is run by a small team of full-time employees and a few regular contributors. We are devoted to bridging the gaps between scientific disciplines to speed the flow of information from the lab bench to the bedside. Our ultimate goal is to facilitate the discovery of a cure. We believe one of the best ways to do that is to bring independent, research-focused news to a professional audience on a platform that fosters discussion and discourse. Help keep us going by visiting our website and clicking on the green “Support MSDF” button next to the “Research Resources” tab on the top right of our screen.

[transition music]

Now to the interview. Dr. Jill Hollenbach is an assistant professor in the department of neurology at the University of California, San Francisco. She met with science journalist Cynthia McKelvey, to talk about KIR in MS.

Interviewer – Cynthia McKelvey

Why don’t we start by introducing what KIR is, how it’s different from the potassium channel and what its relationship is to HLA.

Interviewee – Jill Hollenbach

Well, KIR is an acronym, it stands for killer immunoglobulin-like receptor. These are receptors on the surface on the surface of natural killer cells. They use generally, not in every case, but use HLA as their ligand and they have either an activating or inhibitory effect on natural killer cells.

MSDF

You mentioned in your talk earlier today at UCSF that they are difficult to study. Why is that?

Dr. Hollenbach

Just in terms of their genetic architecture. KIR occupy a complex on chromosome 19, it’s a multigene complex. And so on any individual haplotype that’s one chromosome, an individual can have between 4 and 14 KIR genes. These genes are really recently evolved, and so they’ve kind of arisen in humans as a result of repeated events of recombination and gene duplication. So what that means is that one KIR gene often at the nucleotide level looks an awful lot like another KIR gene. And so we’ve had a lot of issues. A lot of the methodologies that are available right now in terms of sequencing, part of this has to do with a lack of human genome reference alignments, but there has been a lot of difficulty in examining these genes because they look so much like one another.

MSDF

How does that relate to why they haven’t really seen them on genome-wide association studies?

Dr. Hollenbach

There’s a couple of reasons why we don’t see them on genome-wide association studies. One is that, as I mentioned, there haven’t been a lot of good reference alignments, so as a result we don’t actually see a lot of SNP markers on most of the common platforms that are used for genome-wide association studies. And then the markers that are there are often lost to quality control, because we have a lot of gene content variation, which is kind of like a copy number variant. And so if we only see a result for one chromosome, for example, for a given SNP, that is not going to pass general quality control thresholds. And, of course, you have to recognize that when you’re doing these GWAS studies, you’re looking at a hundred thousand, five hundred thousand, a million markers, two and a half million markers, so you’re not going one-by-one and saying, well this KIR-1, we expect to only see one copy or that sort of thing. So it just gets thrown out in the mix with things that don’t pass QC.

MSDF

How does KIR relate to multiple sclerosis specifically?

Dr. Hollenbach

Well, we’re trying to figure that out. So there’s been a small number of studies examining KIR in multiple sclerosis, and what seems clear is that variation in the KIR does play a role in susceptibility to multiple sclerosis. It may play a role in progression; we’re just not sure. There’s not been enough work done to say definitely what’s going on, but there’s enough evidence to say that something is going on. And some of the work that I talked about in my talk today, an analysis of KIR variation along with HLA in an African-American MS cohort, a very large study population, it seems clear that there is some association of KIR variation with susceptibility or protection for multiple sclerosis.

MSDF

Why study the African-American cohort? What does that tell us about MS in general?

Dr. Hollenbach

We want to study them because they’re different from one another; so an African-American population is going to look very different genetically with respect to KIR and HLA from a European-American population. So we want to know two things. We want to know is there something different going on with these genes with respect to disease in these different populations, OR at the same time we want to know is something the same going on? And so we can learn something both from these commonalities and differences, and both can be really important in genetics. So if there’s something that is important that’s specific in the African-American population, we want to know that, and we can only find out by looking at a number of different ethnic groups.

MSDF

Let’s talk a little bit more about interaction between KIR and the HLA ligand, and how that plays in with Bw4. And if we can define all of those things, too, that would be great.

Dr. Hollenbach

Okay. Well, so KIR molecules, as I mentioned before, need to see something, they need to have a ligand on their target cell. We have both inhibitory receptors and activating receptors. The job of the NK cell is to perform immune surveillance. So NK cells kind of wander around the body, and what they’re looking for are cells that don’t look healthy. So what does that look like and what is an unhealthy cell? It’s a cell that is virally infected, it’s a tumor cell. Those are the two main things that NK cells are looking for. And it’s a really important function because they’re part of what we refer to as the innate immune system; it’s the first line of defense against these kind of unhealthy events.

And so what does an unhealthy cell look like? Well, one of the things that happens in both viral infection and tumors is downregulation of MHC class I. That’s what the KIR are looking for. So when an NK cell encounters a healthy cell, it will see HLA class I, it immediately recognizes this is self, this is healthy cell at least in terms of what I’m able to see as an NK cell, and it will move on and it won’t cause any damage to the cell after making contact between the KIR and that ligand.

On the other hand, if the KIR doesn’t see this HLA ligand, the inhibitory KIR, an activating KIR – and we’re still not completely sure what the activating KIR ligands are – but the activating KIR is also bound to something on the surface of this cell. If the activating KIR is bound but the inhibitory KIR is not, what happens is the NK cell is going to lyse that cell which is presumably unhealthy in some ways – tumor or viral infected.

Now HLA class I – actually all HLA molecules – have another primary really important role which is antigen presentation to T cells. Class I molecules present antigen to the CD8-positive T cells, and so that’s how these T cells perform their role in terms of the active immune response. KIRs see a different part of the HLA molecule than the T cell receptors, and so they see kind of this piece of the HLA class I molecule that’s kind of on the side of where the T cell receptors sit. And the variation that they see on that HLA class I molecule can kind of be defined by these broad categories based on the particular amino acid residues. And it’s generally just from two to four amino acid residues that determine whether or not a given KIR can see a given HLA class I molecule.

So one of these epitopes, as we call them – and if they were originally defined on a serological basis because specific antibodies could recognize them – so one of these epitopes is referred to as Bw4; these are epitopes that we mainly see on HLA-B molecules – not all – so depending on the population, human population, may be from 40 to 60 or 70% of HLA-B molecules will have this Bw4 epitope. Some HLA-A molecules also bear the Bw4 epitope. So that’s what some KIR molecules, specifically KIR3DL1, is seeing is Bw4.

The results of the study that I talked about today and what we saw is in this African-American multiple sclerosis cohort, individuals that have both 3DL1 and HLA alleles with the Bw4 epitope appear to be protected from multiple sclerosis. And so we see higher frequencies of this combination in our control population relative to patients. So that suggests a protective effect of that combination, 3DL1 plus Bw4.

MSDF

Where do you see the research going from here?

Dr. Hollenbach

Right now the data that we’re looking at is strictly in terms of carrying frequencies for these particular genes. So these genes are actually highly variable at the allele level, so any given gene like KIR3DL1 has many, many variants that are already known, and likely many variants that we haven’t identified yet because the technology has not been there. The technology is just about now caught up to the point where we are able to examine at the sequence level the variation within these specific KIR genes, and so I think that that’s really the next step. And we’re actually taking steps to start examining this cohort and others in terms of this fine-grained variation in the KIR genes.

MSDF

Very good. Thanks.

[transition music]

Thank you for listening to Episode Thirty-Four of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is vice president of scientific operations.

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

 [outro music]

[intro music]

Host – Dan Keller

Hello, and welcome to Episode Thirty-Three of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.

This week’s podcast features an interview with Dr. Pierre-Antoine Gourraud about the function of human leukocyte antigens and their role in MS. But to begin, here's a brief summary of some of the latest developments on the MS Discovery Forum at msdiscovery.org.

Early in January, the journal Nature Reviews Neurology published a highlights issue of research advances in MS in 2014. The milestones included successful phase 2 trials for simvastatin in progressive MS, new clinical phenotype categories, and more. We summarized each of these advances, supplemented with interviews from some of the authors. Go to the “News and Future Directions” section of our website and click on “Top 8 MS Research Advances of 2014” to read it. And please do make use of our comment section, especially if you believe that we – and Nature Reviews Neurology – failed to list any equally important advances.

Dimethyl fumarate, also known as Tecfidera, may lower CD8-positive T cells in patients with MS, according to a new study out last week. This news follows an earlier story of a patient who died of complications from the rare brain infection, progressive multifocal leukoencephalopathy, or PML, after taking dimethyl fumarate. The drug is known to lower leukocyte levels, including lymphocytes, but many patients are able to maintain normal white cell counts while on the drug. This study showed that even patients with normal leukocyte counts may have dangerously low levels of CD8-positive T cells. These cells are involved in viral immunity, and lower levels of them may leave the gate open for opportunistic infections, such as JC virus, that causes PML.

If you enjoy this podcast and find MSDF helpful, please consider supporting us with a donation. MSDF is run by a small team of three full-time employees and a few regular contributors. We are devoted to bridging the gaps between scientific disciplines to speed the flow of information from the lab bench to the bedside. Our ultimate goal is to facilitate the discovery of a cure. We believe one of the best ways to do that is to bring independent, research-focused news to a professional audience on a platform that fosters discussion and discourse. Help keep us going by visiting our website and clicking on the green “Support MSDF” button next to the “Research Resources” tab on the top right of our screen.

[transition music]

Now to the interview. Dr. Pierre-Antoine Gourraud is the leader of the translational digital medicine group in the Department of Neurology at the University of California, San Francisco. He’s also a distinguished member of our scientific advisory board. He met with science writer, Cynthia McKelvey, to talk about human leukocyte antigen in MS.

Interviewer – Cynthia McKelvey

Let’s begin by defining the major histocompatibility complex and human leukocyte antigen; what those are and how they relate to multiple sclerosis.

Interviewee – Pierre-Antoine Gourraud

So the MHC, the major histocompatibility complex is one of the most important region of the genome. It’s 1000 of the genomes, 3.6 megabase, but it represent about 1% of the total number of genes. So a region that is very dense in genes that are very, very important in neurological functions. It’s also one of the most polymorphic region of the genome, which mean that there are many, many version, many diversity, a lot of alleles, as we call these different forms of a given gene for that particular region of the genome. Basically, it’s encode for or identity or genetic identity, and it has been studied a lot for transmutation. So for multiple sclerosis, since 1972 has been recognized that something in that region had to do with multiple sclerosis risks or the susceptibility; why people are getting multiple sclerosis whatever or not. So back in 1972, researchers realized that people carrying an HLA-DR2 type were actually more susceptible to multiple sclerosis. So doing that in a very simple and comparative manner, we took a bunch of people that have MS, a bunch of people that don’t have MS, and you just see that people that have MS tends to have more HLA-DR2. At that time, the HLAs so the genes that bears the immunity identity of [?] – very important for transmutation again – they were typed by serological techniques. So we were using antibodies to distinguish different types. Over the years, serology has been replaced by PCR-based technique, molecular techniques, and we are now doing HLA typing by sequencing. And for 30 years basically this result has been confirmed, and many additional findings we find the initial association between the MHC region and multiple sclerosis.

MSDF

So you’re looking at a cohort of African American MS patients and comparing them to people of European descent with MS. And, you're seeing some differences in the major histocompatibility complexes with these. And how do those relate to MS? What are they telling you about the disease?

Dr. Gourraud

You know, if we're stepping back a little bit, it's very important to get very large samples to do genetic studies. The more people we are looking at the easier the findings easy to find alleles. So UCSF and other groups in the world have been organizing to coordinate their effort in structuring the International Multiple Sclerosis Genetic Consortium, IMSGC, and we have been really, really successful in gathering large number of MS patients of European ancestry, as well as controls. Within that consortium, UCSF and Dr. Cree and Dr. Oksenberg, have been pushing an effort to coordinate as well African American cohort of MS patients. So we have been working on that, and for the past two to three years we have done a tremendous effort to actually type the HLA of these patients and these controls. And we have gathered more than about 1600 African American MS patients – and we are still collecting them – and roughly 2000 African American controls to do the comparison.

So the first thing we want to do is to see if we are confirming what we see in the European patients – and that is true – we have found  HLA-DRB1 15:01, 15:03 as a specific allele for African American. The HLA-DRB1 03:01 is also to some extent a risk allele in African American. And we also confirm that in the class I HLA-02:01 has a protective effect on MS. So, it's not necessarily obvious, because some of these alleles are actually not found in people of African ancestry, and they also have a much larger diversity. So we are starting to accumulate evidence showing that other alleles that are not present in the Europeans are associated with MS risk. And that’s a very important finding, because now we are in a position where we're going to find structural, functional commonalities between the African American alleles and the European alleles that are both associated to MS.

MSDF

And where do you see the research going from here?

Dr. Gourraud

So one also very important topic that's being working on both in Europeans and African American is trying not to consider HLA on its own, even if we have really put a lot of samples and money and effort in that, but also consider another very complex family of genes that interact with HLA. These are called KIR (K-I-R), and they are receptor at the cell surface of NK cells, the natural killer cells that have a very important role in immune regulation, and it has been reported that NK cells are actually present in the brain in active MS lesions. So we looked at these two system as potentially interacting to define the risk of MS. So we started typing also for these KIR genes in our African American to be able to study at the same time the MHC or the HLA genes, the KIR genes on a different region of the genome, and also the rest of the genome where we've used a simple marker called SNP.

MSDF

That’s great. Thank you very much.

Dr. Gourraud

You’re very welcome. Thank you.

[transition music]

Thank you for listening to Episode Thirty-Three of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is vice president of scientific operations.

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

 [outro music]

[intro music]

Host – Dan Keller

Hello, and welcome to Episode Thirty-Two of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.

This week’s podcast features an interview with Dr. David Holtzman of Washington University in St. Louis about how a protein implicated in Alzheimer’s disease may also have a role in MS progression. But to begin, here's a brief summary of some of the latest developments on the MS Discovery Forum at msdiscovery.org.

We recently added a new data visualization to our growing collection. This one organizes every ongoing MS clinical trial—142 of them—into an interactive bubble chart. The size of each bubble represents the sample size of the trial, and the color indicates if the compound has been used to treat MS before. You can organize the chart 10 different ways, including by phase, compound, and sponsor. Go to the “Research Resources” section of our page and click on “data visualizations” to view it.

Yet another Phase 2 trial on autologous hematopoietic stem cell transplant was published last week. We reported on this trial’s results and how it was different from previous trials we covered. Like the last two studies we reported on, this current study yielded very encouraging results. To view all of the stem cell stories, go to the “news and future directions” section of our website and look for any story with an image of a mouse in a little white lab coat.

New research from the journal Neurology suggests that imaging measurements of the spinal cord and retina independently correlate to disability. Specifically, damage in the two structures was related to visual acuity and to the patient’s ability to discern vibration sensation. The authors suggested that clinicians may want to incorporate scans of the spinal cord and retina into their routine practice.

[transition music]

Now to the interview. Dr. David Holtzman is Chairman of the Department of Neurology at Washington University. He met with MSDF senior science journalist, Carol Cruzan Morton, at a recent Keystone meeting in Taos, New Mexico, to discuss how his work on apolipoprotein Ein Alzheimer's disease may be relevant to MS.

Interviewee – David Holtzman

Most of my career has been focused on trying to understand the pathogenesis of Alzheimer's disease, as well as to develop better diagnostic and treatment methods. However, in doing that – in trying to study the science behind that disease – I've also worked a lot on how normal brain function might be related to not only Alzheimer's disease but just some of the proteins that are involved in both Alzheimer's disease and related disorders.

Interviewer – Carol Cruzan Morton

We're at the Keystone meeting on neuroinflammation in Taos, New Mexico, and at the talk this morning you mentioned that there might be a connection between the ApoE and this protein involved in Alzheimer's and MS. Can you talk a little bit more about how that protein works normally in an Alzheimer's, and how you came to make that connection to multiple sclerosis?

Dr. Holtzman

Sure. Apolipoprotein E first just in terms of a risk factor for Alzheimer's disease ApoE is present as a protein in all of our bodies. It's made in the brain; it's made by the liver; it's at very high levels in the bloodstream. ApoE plays a role in the bloodstream in transporting lipids around the body. It turns out, though, that if the only thing it did was to transport lipids in the blood then you would probably only need to produce it in the liver so that it was secreted into the blood. But interestingly, it's also produced in several other organs: the ovary, the testes, the brain, and a few other places. So in those other organs, it doesn't probably have exactly the same function that it does when it's made by the liver. But the form of the lipoprotein that's in the brain that ApoE is within is somewhat different than it is, for example, in the bloodstream. It's in what's called HDL or high-density lipoproteins in the brain.

MSDF

That's a good thing, right?

Dr. Holtzman

That's the good cholesterol. That's the good cholesterol in the blood. In the brain, it's not entirely clear what these HDL lipoprotein particles are really doing. So, for example, if ApoE is absent from the brain of a person, and there are people that have genetic mutations, they have no ApoE in their body…

MSDF

Completely gone.

Dr. Holtzman

Completely gone. And they have developed serious problems with cholesterol buildup in their arteries because they can't clear big lipoprotein particles from their blood, but their brain is okay, no problem. The people are born normal; brain is okay. And there are probably other proteins in the brain that may be able to takeover for its function in the brain; whereas in the blood that's not the case.

MSDF

And when it goes wrong in Alzheimer's, what's happening…?

Dr. Holtzman

So that's a different issue. So in Alzheimer's disease, there's no lack of ApoE. In humans, there's three different flavors of ApoE: ApoE2, ApoE3, or ApoE4. And there's a very, very subtle difference between the ApoE2, 3, and 4; just really, really small difference. So brain function in people that are of different ApoE types is normal when they're born and when they grow up and as adults. But for some reason – which we'll talk about in a moment – when people have the ApoE4 form of ApoE, it causes a higher risk for Alzheimer's disease probably because it's promoting the buildup of one of the proteins that's really important in causing Alzheimer's disease earlier. So this amyloid protein that builds up in Alzheimer's is strongly influenced by the form of ApoE that you produce. So if you make the E4 form, it's probably because amyloid doesn't get cleared away as well; it builds up earlier. And if you have the ApoE2 form, which is protective against Alzheimer's disease, it pushes out the development of amyloid deposition until very old ages, if ever. That may be something that's related to Alzheimer's disease that's distinct from what it might do in other diseases of the brain like MS, for example.

MSDF

How did you make that connection to MS?

Dr. Holtzman

Right. So over the years, there's been a number of scientists and physicians around the world who have studied the many possible functions of ApoE in the body. And for gosh it's been about 30 years or so, there's been reports that one of the things that ApoE does is to influence inflammatory cells: T cells, macrophages, etc.

MSDF

All over the body or in the brain and spine?

Dr. Holtzman

Yeah, in different locations actually. It's never been completely clear exactly what ApoE is doing to the immune system. A lot of studies individually show effects, but it's not entirely clear what it's doing. And so, I got interested in this personally a few years ago there was a prominent paper published suggesting that one of the things that ApoE does to the immune system outside the brain is to help present antigens to the immune system if they contain lipids. And so, that caught my attention because, one, ApoE carries lipids. And just naively I thought well if it helps present lipid antigens in multiple sclerosis the antigens that are being attacked generally are the lipid related antigens.

MSDF

The myelin.

Dr. Holtzman

The myelin, right, exactly. So I thought well that seems, you know, maybe there's something to this that one could study in relation to MS because of that.

MSDF

And then how did you go about asking those question? Where did you start?

Dr. Holtzman

Basically, I thought alright, well a lot of people who work on MS if they use animal studies use the model EAE. So we thought well some of my colleagues at Washington University have been using the EAE model for years – like many people have – and so we thought well the obvious experiment to try first is just compare animals that express ApoE in their body versus those that don't. And simply ask the question is there anything different about EAE in an animal that lacks ApoE or not? And so, first, we started working with Anne Cross and then later with Greg Wu together who are experts in using animal models of MS. And ultimately published findings showing – and a few other groups have worked on this, as well – showing that there appears to be decreased clinical severity of EAE in a slightly later onset of disease in animals that lack ApoE.

MSDF

And what does that tell you…there might be a role or…?

Dr. Holtzman

Obviously many other studies would need to be done to know if it has a role in human MS. But once we found that, particularly Greg's lab began to ask the question well if that's true what's the mechanism? If there is a mechanism that we could hone in on, is that something that seems logical based on what we actually know about ApoE already? And so, the things that kind of came out of our first series of studies was that – unlike what I initially had thought from this earlier paper – it doesn't appear that ApoE is modifying antigen presentation of cells or the ability of T cells to react against the brain. But something once T cells do get in the brain to attack myelin and other components, there's something about that ApoE is acting on at that point. It could be that it's involved in allowing the myelin to repair, or alternatively it could be that when T cells get into the brain and interact with other cells in the brain – like other immune cells like microglial cells or dendritic cells – that that interaction is altered by ApoE within the brain. That might make sense given that ApoE is highly expressed by macrophages outside the brain, and inside the brain it's highly expressed by what are called activated microglial cells. So kind of the macrophages of the brain. So that's where we kind of are now, and I think there's a lot more studies that could be done to really understand both that interaction as well as whether human ApoE causes the same effect that we saw in animals as mouse ApoE. Because they're not exactly the same; they're similar but not the same.

MSDF

Is there other evidence connecting ApoE or its various forms with MS?

Dr. Holtzman

There are human studies that have been done trying to ask the very simple questions of is the ApoE4, which is a risk factor for Alzheimer's, is that over represented in MS? Or is the ApoE2 form, which is under represented in Alzheimer's, is that protective against MS? And the studies on this some have suggested effects, some haven't. There's no clear answer. But I think if ApoE is involved in MS, it would be less likely to be involved in whether you get MS but more likely involved in the progression of the disease. And I know in the MS field one of the big areas now – now that there's so many studies and as well as treatments that have emerged that are quite effective at suppressing the initial phases of MS, the immune response phases – a lot the work is going into understanding this prolonged progressive phase of MS. And that's where ApoE could be important in sort of the repair and recovery of neurons and axons, for example. Because the fact it transports lipids between cells, maybe it has something to do with recovery of the brain after injury. And that's been speculated on for some time, although not as much work on that has been done in MS.

MSDF

Has it been speculated on in MS or MS and Alzheimer's both or…?

Dr. Holtzman

No, it's been speculated on after a variety of different brain injuries that it plays a role in redistributing lipids in the brain after injury, and that might be promoting recovery. So one possibility that still hasn't really been tested that I'm aware of in models of MS or in human MS is to whether that really happens for ApoE in the human brain or animal models.

MSDF

Can that be tested now?

Dr. Holtzman

Absolutely, absolutely. Those are some of the studies that I think are really critical as the next step.

MSDF

Is it conceivable that the body of knowledge for Alzheimer's research on ApoE might yield a treatment for progressive MS?

Dr. Holtzman

It's possible. I mean a lot of the understanding of what ApoE might be doing in the brain has really expanded because people have been studying Alzheimer's disease and its relationship with ApoE. So I can't imagine it wouldn't help with that because we've learned a lot so far.

MSDF

Are there other treatments in the pipeline for Alzheimer's related to ApoE?

Dr. Holtzman

There are. There's not too many things yet that have reached human trials, but there are groups trying to alter the level of ApoE in the brain or to alter its receptors in the brain as potential treatments for affecting Alzheimer's disease. So yeah, I mean those are the kind of things, as they advance, depending on what's found in regard to the relationship between ApoE and MS could be tried in MS. I don't see why not.

MSDF

That's interesting. What else should I be asking?

Dr. Holtzman

I think what scientifically what I think is really important to still sort out in this area is that when the innate immune cells of the brain – the microglial cells or even macrophages when they get into the brain – they produce tremendous levels of ApoE when that happens. And I think understanding what that protein is really doing in that setting could provide insight into future treatments. So that's what I think is really fascinating to try to understand.

MSDF

Well if it happens in Alzheimer's, as well, it happens before the blood-brain barrier breaks down and then after it, it sounds like.

Dr. Holtzman

Well, in MS, it's probably occurring after there's cell entry into the brain. But the upregulation of ApoE by these innate immune cells is much higher in MS than it is in Alzheimer's disease.

MSDF

Oh, is that right?

Dr. Holtzman

Yeah, yeah.

MSDF

That's interesting. That's even more interesting.

Dr. Holtzman

Yeah, I know. That's why it's really, really fascinating. I think one of the figures from the paper that we published last year from Greg's lab showed that the level of ApoE increasing in microglial cells versus similar cells that are present in the spleen of an animal is like 25 times higher in the setting of an EAE model than normal. So it's really, reallyhigh. Is it really doing anything, or is it just a byproduct? I suspect it probably is doing something. So that's what I think would be really interesting to figure out.

MSDF

Thanks. Well I appreciate your taking time out at the Keystone meeting to talk with MS Discovery Forum.

Dr. Holtzman

Yeah, it's great. Well good luck. MS is such a…the treatments that have been evolving are so exciting compared to Alzheimer's disease where we don't yet have good treatments. So I think there will be soon, but I think it's a great opportunity to even advance for ...

MSDF

Is there a chance that the reverse could be true? That treatments existing for MS would be helpful in Alzheimer's?

Dr. Holtzman

That's a good question. I don't know if any of the frequently used ones where you're preventing cell entry into the brain necessarily would be useful for Alzheimer's. But like one of the new drugs, Tecfidera, this oral medication does do some interesting things to cells in the brain that might be useful in a disease like Alzheimer's. So maybe there will be some things that we can translate.

MSDF

I appreciate it. Thank you so much.

Dr. Holtzman

Thank you.

[transition music]

Thank you for listening to Episode Thirty-Two of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is vice president of scientific operations.

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

[outro music]

[intro music]

Hello, and welcome to Episode Thirty-One of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.

This week’s podcast features an interview with Dr. Lloyd Kasper about the gut microbiome and its role in MS. But to begin, here is a brief summary of some of the latest developments on the MS Discovery Forum at msdiscovery.org.

Last week our parent organization, the Accelerated Cure Project, launched its latest endeavor called “iConquerMS.” iConquerMS aims to enroll 20,000 people living with MS to play an active role in research, empowering them to securely submit their health data, influence the studies that are carried out by the initiative, and stay informed about the research. Visit iConquerMS.org for more information.

Vision and sensorimotor problems go together in some MS patients. A recent publication in the journal Neurology examined the relationship between MRI measures of the spinal cord and retina in patients with MS. The investigators found some correlation between the two types of metrics, but they also found that damage in each structure had independent relationships with disability. Read the full story in our “news and future directions” section.

And lastly, our previous podcast contained an error. We mentioned a story about a proof-of-concept study of a novel way to monitor lesion repair. However, the story was withheld from publication due to a delay in the release of the research article. The story is now live on our website.

[transition music]

Now to the interview. Dr. Lloyd Kasper is a faculty member of the Geisel School of Medicine at Dartmouth College. He met with MSDF Executive Editor, Bob Finn, to talk about his research on the gut microbiome and MS.

Interviewer – Robert Finn

Dr. Kasper, welcome.

Interviewee – Lloyd Kasper

Thank you.

MSDF

So to start, why on earth would someone interested in a neurological disease such as MS concern himself with bacteria in the intestines; what’s the connection?

Dr. Kasper

That’s actually a very valid question. And the answer to that question is pretty straightforward, is that there’s a very clear brain-gut access so that the brain talks to the gut primary modulating the physiology of the gut through secretion of a variety of molecules, vasoactive proteins, etc. That in turn affects the motility of the gut. By affecting the motility of the gut, you also affect everything that’s inside the gut, which is – as you mentioned just previously – the 100 trillion bacteria that each and every one of us in this world has. And those bacteria in response to the changes in motility shift their behavior, because these are living organisms, and they secrete a wide range of metabolites.

For the purposes of simplicity, you can look at those metabolites and the effect of those various metabolites on the immune system, taking into account that the gut is the largest immune system in our body – 80% of our immune cells are in the gut. So you’ll have this clear interaction between the brain, its activity physiologically on the gut, and the gut’s activity on the bacteria, and then the bacteria’s activity back on the immune system which leads to issues related to the brain.

MSDF

So you partly answered my next question. There are microbiomes in other places besides the gut – the skin, the urinogenital tract, etc. Do those other microbiomes have any affect or any relationship to multiple sclerosis, do you think?

Dr. Kasper

First of all, the association between the gut microbiome and MS has not yet been fully established, there’s experimental data that would suggest that there is a relationship between the two but that’s still at the experimental level. There really has been very little exploration of the other microbiomes within the body. Remember, the microbiome is not just the microflora. What the microbiome is is the genome of the flora in its relationship to the genome of its host. So when you look at the genomics of MS, for example, in the host – which there’s a lot of work that’s being done – you’re only looking at a fraction of the genetic material that’s involved in this relationship between the gut and the body that it’s in OR any of the other sites that we have microflora – our mouth, as you pointed out; our ears – inside of our ears; our lungs. Those are all areas that bacteria in our body exists in balance with us to achieve a homeostasis. The reason for looking at the gut microbiome is that because it’s the largest, probably the most complex as well.

MSDF

So you focused much of your attention on a single bacterial species. Let me see if I pronounce this correctly – Bacteroides fragilis– am I close?

Dr. Kasper

Correct.

MSDF

And a single substance that it produces, polysaccharide A, or PSA – which has no relation to prostate specific antigen. Why are you focusing on that species and that product?

Dr. Kasper

Well, there is mounting evidence that there are several phyla that colonize the gut. The two major phyla of interest are Firmicutes, which are gram-positive aerobes, and Bacteroides, which are gram-negative anaerobes. I’m talking about at the phyla level over which there is no kingdom, phylum, class, order, family, genus, species. Under each one of those phyla there are many different species. We’ve focused in on primarily Bacteroides because Bacteroides fragilis is a very common commensal that essentially inhabits in the neighborhood of 80-90% of all mankind in the world. Bacteroides as a phyla has been associated with the induction of regulatory T cells. Regulatory T cells live in the colon, in and around the colon, and that’s where Bacteroides live. And it’s been shown that Bacteroides as a phyla have the capacity to drive regulatory T cells.

The reason it’s important in MS is because there is a known deficit in the regulatory T cell population in patients with MS. And we chose Bacteroides fragilis because of all the Bacteroides species, that’s the one that we actually know most about immunologically. There’s at least 20 or 25 years’ worth of very, very important data that shows how this particular molecule, this polysaccharide A – and it’s a polysaccharide, it’s not a peptide, it’s a polysaccharide – how this polysaccharide can drive the immune system to a regulatory phenotype that’s associated with the induction of regulatory T cells, production of IL10, all those factors which are important in MS which we know are deficient in those with MS.

MSDF

When you say drive the immune system, drive T regs, what do you mean by that?

Dr. Kasper

Basically, these bacteria have the capacity to convert effector cells, which would be CD4 positive CD25 negative cells to a regulatory phenotype, which would be CD4 CD25 positive associated with sort of the standard-bearer of regulatory cells, which is Foxp3, which is a nuclear antigen that’s been characterized with it. So this molecule has a remarkable capacity to do that both in vivo and our studies show you can do that actually in vitro as well. So you can take cells that are negative that would be considered naïve or effector-type cells, culture them with this PSA molecule, and convert them to regulatory cells which we know are important in controlling the disease.

MSDF

So remind me whether you want more or fewer of these regulatory T cells.

Dr. Kasper

It depends where you are in life. To give you sort of a circumstantial argument, we know that Firmicutes, which is that other major phyla, has been associated with a number of disease states, including obesity – just to name one – atherosclerosis, but we also know that the Firmicutes have the capacity to drive IL-17. The regulatory T cells are cells that control the IL-17 response, so it’s important to have regulatory T cells to control the IL-17. We know experimentally that IL-17 drives the experimental form of multiple sclerosis EAE, and there is mounting data – and pretty conclusive, I think – MS is probably at least in part driven by IL-17 cells. So you need these regulatory T cells to control that IL-17 response which is probably being driven by the Firmicutes population. And I’m oversimplifying this, because you remember, you’ve got a hundred trillion cells downstairs making god knows how many different metabolites with over a million genes. So what I’m presenting to you is a very simplified version of this remarkably complex organ.

MSDF

So is this leading toward clinical utility for polysaccharide A?

Dr. Kasper

We hope so.

MSDF

Can you tell me more about that?

Dr. Kasper

Well, again, our experimental data – at least in EAE – demonstrates that animals that have been induced with EAE are protected by this polysaccharide. Animals that have EAE, we can therapeutically treat them with this. So this is the first demonstration that a commensal-derived bacterial product that’s within essentially pretty much all of mankind has the capacity to induce regulatory T cells. We don’t know if MS patients are deficient in this or they have the genetic makeup that they can’t respond to it, or whatever it may be. As I said, there’s a real complexity. But the simple observation as we know is that if we take animals that are susceptible to EAE and we treat the prophylactically or therapeutically, we’re able to protect them very, very nicely against the disease process.

And now we have preliminary data in humans that we can take human cells in vitro out of a person and we can drive those human cells from an effector CD4-positive CD25-negative phenotype to a regulatory phenotype by this molecule; just five days of exposure and you see this very nice conversion that’s associated with increased IL10 protection, etc.

MSDF

Do you imagine that the PSA molecule itself, if drug development goes on, is there any chemistry that needs to be done before it might possibly be therapeutic?

Dr. Kasper

A lot of the chemistry has been done. We have a pretty good idea of what the molecule looks like, it’s a repeating polysaccharide chain. And we know what the conditions are at least in animals as far as innate response molecules – TLRs, toll-like receptors, etc. So as far as the molecule itself, I think we have a pretty good understanding. As I said, there’s about 20 years’ worth of very solid biology behind this molecule. So how far we are away from the clinic at this point is a matter of time, resources, and money to be able to move it from the experimental stage that we’re in into the clinic.

MSDF

So you’re not the only research group working on the connection between the gut microbiome and multiple sclerosis. I wonder if you can talk a little bit about how your research fits in with the various other approaches that are going on.

Dr. Kasper

Our research has been focused primarily on immune regulation – how to get the disease under control, at least experimentally and hopefully in MS patients. Most of the other labs are looking primarily at what bacteria or bacteria populations are responsible for affecting the disease; what’s driving the disease. We’ve sort of kept away from that because we were fortunate in being able to find this one molecule derived from a bacteria, as I said, that much of mankind is colonized with, so we’ve been focused mostly on how to regulate the disease rather than what’s driving the disease.

MSDF

Now, as you know, there’s been a lot of talk and controversy about the role of diet in multiple sclerosis. Do you think that gut bacteria and the substances they product may provide that missing link connecting diet with MS.

Dr. Kasper

I think that diet’s going to turn out to be one of the more critical environmental factors that’s associated with the disease process.

MSDF

Can you say a little bit more about that?

Dr. Kasper

Well, if you look at all the risk factors that we know for MS, that being genetics, obesity, smoking, gender – just to name a few – there’s about six or seven of them. Every one of those risk factors is associated with the microbiome. The common denominator for all the risk factors we know so far in MS is the microbiome, and that includes genetics. As I said, the microbiome is a two-way street; it induces things in us and we do things in turn to it, so it’s a binary system. So our speculations – and we just had a paper published in FEBs – Federation of Experimental Biology – is we’re speculating that the gut microbiome is the major environmental risk factor for MS because it includes all of the known risk factors.

So how can you adjust that? Well, the most logical way is diet, right, because it’s the change in the human diet over the last hundred years that may be accountable for the rise in the disease process. It may also be the change in the diet in Africa as well as Asia which were relatively unknown for MS, but now the incidents in Asia as well as in Africa is approaching about the same as it is in the United States and Europe. So as diet has changed, so has the incidence of the disease gone up. So I’m speculating that diet will turn out to be a very important factor in controlling the microflora, which in turn allows for the balance, the homeostasis, in individuals.

MSDF

Well, very interesting. We’ve come to the end of our time, but is there anything you’d like to add, any important questions that I haven’t asked that I should have asked?

Dr. Kasper

No. I think the question about the diet, you know, where do you go from here? Because it’s going to take years and years for scientists and clinicians to sort out what’s actually going on in the microbiome. We’re at the tip of the iceberg in this really, because not only is it the immunology that’s important but it’s the physiology and the physiologic changes that the gut microbiome may be creating in people. So as we get better definition of what activities are going on in the microbiome, the greater the likelihood we’ll have of understanding a whole range of human diseases. And not just MS, but that’s all other autoimmune diseases, cancer, obesity, you know, it’s a long list.

And it may ultimately turn out that it’s a clue to our understanding of cancer, for example, because as the microflora shifts as we grow older – which it does – perhaps what we’re seeing is that early on we have bacteria that induce inflammatory processes – which is why MS is a disease of young people – that tends to peter out as you get older. It’s a well-known thing. It doesn’t go away but it tends to peter out. But that may be parallel to the shift in the microflora that’s going on. So early on in the western diet you’re having mostly Firmicutes. As we get older that shifts to more of Bacteroides, which has more regulation. What does more regulation equal? Well, you’re down-regulating the immune system, and as we get older what do we become susceptible? Cancer. So there’s a real balance that’s going on here. And I think a lot of the clues to human biology as far as disease state are going to ultimately be related to the microbiome.

MSDF

Dr. Kasper, thank you very much.

Dr. Kasper

Thank you.

[transition music]

Thank you for listening to Episode Thirty-One of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is vice president of scientific operations.

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

 [outro music]

[intro music]

Hello, and welcome to Episode Thirty of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.

This week’s podcast features an interview with Dr. Seema Tiwari-Woodruff about estrogen in animal models of MS. But to begin, here’s a brief summary of some of the latest developments on the MS Discovery Forum at msdiscovery.org.

Last week, we reported on the results of another clinical trial for hematopoietic stem cell transplantation in relapsing-remitting MS. Compared to the “halt-MS” trial, which we reported on in January, this study used a less aggressive conditioning approach. Patients involved in the study demonstrated improvement in EDSS scores, and eighty percent of them were relapse-free at four years. The results raised important questions about how to prep MS patients for the transplant. Visit our “News and Future Directions” section to read the full story.

A recent study published in the Multiple Sclerosis Journal demonstrated a potential new way to monitor lesion repair using standard MRI techniques. Clinical trials usually look for new lesions in brain scans to monitor drug efficacy. Lead author, Daniel Reich, told MSDF it’s more important than ever to be able to visualize changes in tissue since drug development is shifting towards neuroprotection and repair.

We’re also pleased to announce that Daniel Reich is one of two new members of our Scientific Advisory Board. Dr. Reich is the director of the Translational Neuroradiology Unit in the National Institute of Neurological Disorders and Stroke, part of NIH. Our other new board member is Deborah Backus, an expert on rehabilitation who is Director of Multiple Sclerosis Research at the Shepherd Center in Atlanta, Georgia. Read their full bios in our “Who We Are” section under the “About Us” tab.

[transition music]

Now to the interview. Dr. Tiwari-Woodruff is an associate professor of biomedical sciences at the University of California, Riverside. She met with MSDF editor-in-chief, Bob Finn, to talk about her research on estrogen and multiple sclerosis.

Interviewer – Robert Finn

Dr. Tiwari-Woodruff, welcome.

Interviewee – Seema Tiwari-Woodruff

Thank you.

MSDF

So what is the connection between estrogen and MS?

Dr. Tiwari-Woodruff

It’s an interesting connection between estrogen and MS, because estrogen is actually a part of life in a way that our brains require it, our bodies require it at every moment of our life, I should say. Many years ago it was found that relapsing-remitting patients had less relapses when they were pregnant, and the causes of that was potentially estrogens – high levels of them – or progesterone or vitamin D. Many researchers went ahead and looked at those high levels of pregnancy estrogens called estriol and found that high levels of estriol were the reason why these women patients had lower levels of MS symptoms.

So eventually down the line, estrogens were parsed out of which estrogen was better. And it turns out that one type of estrogen, which is the estrogen of the alpha, is more immunomodulatory – it actually suppresses the immune response – and that is probably what makes MS symptoms better versus estrogens of the beta ligand was known not to have that much immunomodulatory effect; instead, it was actually directly neuroprotective. So estrogens of the alpha and beta both seem to have an effect on various cell types which are involved in multiple sclerosis.

MSDF

So if estrogen seems to be protective in pregnant women with MS, why not just use estrogen, or an analog like estriol or estradiol, as a treatment?

Dr. Tiwari-Woodruff

That’s a very good question. And, first, these therapies were thought that we were going to use those first, and a lot of clinical trials were going through with that. But what happens with high levels of estrogen is there are two things which are important to know. One is they have a feminizing effect, and the second one is they have a preponderance for causing uterine cancer or breast cancer. So you don’t want to stimulate those two types of cancer. So high levels of estrogen could be dangerous in that aspect. So that is why we don’t want to use that as potential therapy.

MSDF

So you’ve done a lot of work with a specific estrogen receptor agonist called indazole chloride. First, tell me how you came upon this compound.

Dr. Tiwari-Woodruff

So estrogens of the beta ligands are not just being looked at for multiple sclerosis, they were being looked at as a potential therapeutic for menopause – hot flashes included – rheumatoid arthritis, and other impairments like prostate cancer, etc. So there were quite a few chemists who were coming up with various different types of estrogen receptor beta ligands. So while I was doing my work with mouse models of MS in generic estrogen receptor beta ligand, which was the DPN – diarylpropionitrile – a study came out which was actually on indazole chloride which was developed by a chemist, John Katzenellenbogen; he’s done a lot of work on developing these molecules. And this particular compound showed that it decreased activation of astrocytes and microglia; this was published in Cella few years back. And we met at a meeting, John Katzenellenbogen and myself – we were giving a talk at the same time in a meeting in Stockholm – and we decided to talk to each other. And he said, “Your research is very intriguing on estrogen receptor beta ligand, would you like to try this out?” And that’s how I got my hands on the indazole chloride. And we did some preliminary studies and showed good results. Then we decided to embark on a full-fledged study which was published in PNAS.

MSDF

So you used indazole chloride in two different mouse models of MS, and you used it both prophylactically and in mice that are already showing symptoms. What did you find?

Dr. Tiwari-Woodruff

So prophylactically when you use a compound, you are actually trying to see if you can inhibit the symptoms which are going to come up when you induce a disease, and that is all good. But when you are talking about patients who come to see the doctor, they’re always coming in with symptoms, so they already have the disease ongoing. So the second paradigm where you give the drug when the disease symptoms are already there is closer to what humans are going to be able to see. So the nice thing about indazole chloride was that, prophylactically, definitely it made the mice better, but therapeutically also; they were able to decrease the disease symptoms by nearly 50%.

MSDF

What is the significance of the fact that it seems to work on two different mouse models of MS?

Dr. Tiwari-Woodruff

So when you’re looking at a drug especially in a disease like multiple sclerosis which has two major components – one is inflammatory component and another one is a neurodegenerative component – if you can show that this drug is working in one way or both ways would be very useful for developing better drugs or better treatments. So what we did was when we treated the mice with indazole chloride, in one mouse model which is the experimental autoimmune encephalomyelitis which contains both the inflammatory and the neurodegenerative component, we saw a decrease in the disease symptoms. But we couldn’t tell if the indazole chloride was working in the inflammatory component or the neurodegeneration component, because it showed effect on both.

So we went to a second mouse model which is the toxic cuprizone diet model which doesn’t have a primary inflammatory component. The disease starts with oligodendrocytes, the cells which make the myelin. They die when you feed this diet to the mice, so they have massive demyelination in regions of the brain. When we gave the drug during the remyelination phase, we found that indazole chloride was able to remyelinate the axons better when the drug was present versus when it was absent. So this actually showed us that indazole chloride has two arms to it. One, it inhibits the inflammatory component and the second, it inhibits the neurodegenerative component independent of the inflammatory component.

MSDF

Is it also sort of confirmatory? The EAE is not a perfect model of MS and neither is the cuprizone mouse model, but does it make you feel better that these two completely different models are showing similar effects?

Dr. Tiwari-Woodruff

Absolutely, you really hit the point where… We are always looking for the best model for multiple sclerosis, but because the disease is so complex no one model can be said that it’s 100% mimicking multiple sclerosis. So for us to see that demyelination which occurs both in EAE and the cuprizone model was improved – we actually saw remyelination in both models – really gave us hope that this drug could be directly acting on oligodendrocytes which are forming the myelin, which is the cause of major mode of dysfunction in multiple sclerosis.

MSDF

So does indazole chloride help these mice a little bit, or does it help them a lot?

Dr. Tiwari-Woodruff

So that’s a very good question. Similar to what you might see in the patient population, in the mouse model of MS, especially in the EAE model, the disease is not consistent. So the lesions which appear in the brain of EAE animals are very diverse, unlike the cuprizone model where the demyelination is very consistent. So when you’re looking at these mice, especially in the EAE cohort, if the animal is really, really sick, you actually see the disease symptoms go down just a little bit. But if the animals were sick to the middle level, they actually showed a bigger difference, they showed better recovery. And we hypothesize that the axons which have been injured to the point of no return, if the axons have been demyelinated and injured, it doesn’t matter now when you give them therapeutic drugs, these are not going to improve. So there are certain number of axons in the brain which drop out and we don’t see recovery in those. But said that, overall we still saw a significant increase with indazole chloride treatment in both models.

MSDF

Have you done histology?

Dr. Tiwari-Woodruff

Yes. We’ve done histology, we’ve done electron microscopy. And we do one more thing my lab is very good at, we do electrophysiology. Because one of the things we always think is when you look at remyelination you can see myelin coming up, but is the myelin functional? If the axons can conduct faster or better, then you know that the myelin which has covered the axons is functional. So we do all three. And we also include behavioral testing. So one of the tests we included which a lot of people use is a Rota rod; it’s a motor test to show that the mice can stay on the Rota rod much longer after treatment with indazole versus just the vehicle.

MSDF

Do you see any side effects?

Dr. Tiwari-Woodruff

So that’s interesting. We did not see any side effects in these mice. Agreed, we treated them up to 60 days, we haven’t treated them longer than that, plus we were giving them at a 5 mg/kg/day concentration. So we didn’t see any kind of toxicity. But said that, we still need to do those studies in a thorough way before we can safely say that they had no side effects.

MSDF

So what’s next in the development of indazole chloride as a potential MS treatment?

Dr. Tiwari-Woodruff

So indazole chloride is a good target. And while these studies were going on last year, John Katzenellenbogen and myself, we were talking about how are we going to proceed with this because we were seeing really good results; this is even before I published the paper. And he said what would you like to do? And one of the things we said was is it possible to make better analogs of this compound which are going to be more specific, could be used in a lower concentration and may have a better therapeutic outcome?

So he came up with four analogs which he has sent to me, and we did some preliminary studies to see if they were toxic to cells in culture, because that’s the first thing you do. And they have no toxicity in cells, they actually have shown to behave well with proliferation – depreciation of the cell – and we haven’t seen more cell death or less cell death with them. So we are very excited about that. So coming next month, we are actually going to start treatment of EAE animals, and once that goes through the goal is to do toxicity studies on the two best compounds and see if we can find a company so we can have a backing on these drugs for potential human trials. It’s a couple years from now, at least – it could be even more – but we are actually moving in that direction.

MSDF

Dr. David Baker in a commentary on his multiple sclerosis research blog seemed less than enthusiastic about indazole chloride. He suggested that many compounds seem to work similarly in mouse models. How do you respond to that criticism?

Dr. Tiwari-Woodruff

So Dr. Baker has a very good point on saying that there could be many compounds which are good in EAE but they fizzle out and they don’t go up to clinical trial. I disagree on one point where it comes to indazole chloride, because we have precedence of estrogens showing good therapeutic indication in humans; there were clinical trials done in UCLA where they showed that there was improvement with estriol treatment. And estriol does target both ER-alpha and ER-beta – ER-beta a little more than ER-alpha – so I’m very confident that what we are seeing with estrogen receptor beta is not a fluke. And because it’s a steroid and a small molecule, it does not seem to have a lot of toxicity involved which could be somewhat which is brand new. So we’ll see. I hope Dr. Baker’s wrong and we do manage to get this drug to human patients and we see therapeutic efficacy in them.

MSDF

Dr. Baker also said that a critical experiment had not yet been done. And let me quote from his blog post. He said, “The development of demyelination should be allowed to occur after this damage has abated, then punitive remyelinating drugs should be given.” How do you respond to that?

Dr. Tiwari-Woodruff

Very good point made by Dr. Baker, but I have actually addressed those in the PNAS paper. We part off particularly this aspect of the disease. So the prophylactic treatment was before the disease started; that is what he’s mentioning in the blog. The second part is what is important where EAE disease was induced, and after peak disease had occurred we gave the drug, indazole chloride. At the peak disease, we actually see increased inflammation, but alongside with that we see demyelination and axon degeneration. So the damage has already started. The drug treatment after that is what caused the disease to get better. We saw increased conduction, we saw increased remyelination, and less axon damage.

Similar to that, we also did the experiment in cuprizone. The treatment paradigm was as such: We actually had nine week of demyelination ongoing in the cuprizone model, which is very chronic; it’s chronically ongoing where you have quite a bit of damage of the axons and you have acute demyelination. During the remyelination phases where we gave the drug either to one group and vehicle to the other group, what we saw was that the drug treatment, indazole chloride, actually increased remyelination and decreased axon damage. So I think Dr. Baker was trying to make a point on we haven’t done the right experiment, but I think we have done the right experiment. And further research with indazole chloride will let us know if this is a good drug or not.

MSDF

Dr. Tiwari-Woodruff, is there anything you’d like to add?

Dr. Tiwari-Woodruff

I would like to add one more thing. We have actually looked at indazole chloride in optic neuritis – EAE-induced optic neuritis – and we are going to be publishing a paper fairly soon showing that in optic neuritis we see less inflammation in the retina and increased remyelination in the optic nerve. So I’m very confident that it’s not just a phenomenology in one part of the brain which we picked last time – it was the corpus callosum – that we see increased remyelination and decreased damage caused by EAE with treatment of indazole chloride.

MSDF

Well, thank you very much.

Dr. Tiwari-Woodruff

Thank you.

[transition music]

Thank you for listening to Episode Thirty of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the non-profit Accelerated Cure for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is vice president of scientific operations.

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

 [outro music]

[intro music]

Hello, and welcome to Episode Twenty-Nine of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.

This week’s podcast features an interview with Dr. Monica Carson on funding research in MS. But to begin, here is a brief summary of some of the latest developments on the MS Discovery Forum at msdiscovery.org.

Glatiramer acetate and the interferon betas appear to be clinically similar, according to a new study in the Multiple Sclerosis Journal. This study follows on the heels of a Cochrane meta-analysis we covered earlier in 2014 that found similar results. Instead of performing a meta-analysis, though, the researchers of the MSJ article used data from over 3,000 patients in the MS Base database. They found very little difference in annualized relapse rates over 10 years, though glatiramer acetate and subcutaneous interferon beta 1-a did eke out a statistical win over the other interferons.

Together, MSDF and our non-profit publisher, Accelerated Cure for Multiple Sclerosis, are committed to speeding the pathway toward a cure for MS. Among the news and resources we provide is a list of more than two dozen tissue repositories, including one maintained by Accelerated Cure. Visit our website and click on the “tissue repositories” button under the “research resources” tab to browse through repositories from all over the globe.

Another part of our goal in working faster toward a cure is to provide a place where researchers can share their experiences and expertise with one another and also debate controversial issues in MS research. We encourage researchers and clinicians from all disciplines to log onto our forum and discuss their latest research, techniques, and discoveries. We also encourage you to help keep us up-to-date on your latest work by e-mailing us directly. Send information you’d like to share on job postings, meetings, funding opportunities, or other news to editor at msdiscovery.org.

[transition music]

Now to the interview. Dr. Monica Carson is director of the center for glial-neural interactions at the University of California, Riverside. She met with MSDF editor-in-chief, Bob Finn, to talk about the current state of funding in MS research.

[Interview]

Interviewer – Robert Finn

Dr. Carson, welcome.

Interviewee – Monica Carson

Thank you.

MSDF

So let’s stipulate that there’s never enough money available for funding any area of research adequately. On a scale from bad to awful to dire, what is the state of funding for MS research?

Dr. Carson

I would say it’s better than maybe other areas, but all areas of research, I feel, are dire, so I do not want to make MS research sound worse. It’s probably actually better because individuals can see the value of research in disease-oriented research programs. So in a worse situation, it’s good.

MSDF

So there are essentially three sources of research funding. There’s the government; there are nonprofits; and then there are for-profit companies, mostly pharmaceutical companies in the biomedical area. How are each of these doing in funding MS research?

Dr. Carson

There are objectives in all of these. There’s always been a long-term funding priority in NIH NINDS. There’s also out of various objectives that are perhaps nontraditional for those of us who came up as NIH-funded investigators, such as the DOD and various congressionally-mandated research programs. There are much more funding, I think, also in private foundations. Funding in biotech and pharmaceutical, I think, has been the one area that has dropped severely over the years, and that one is not an area that I think one can count on, that is going to be something targeted when you have a proposal. And then you do have to work through the ethics and various other aspects of that.

That said, the National Multiple Sclerosis Society has really shown a very nice model of partnering with pharmaceuticals with their Fast Forward program. I’ve served on those panels and they are really wonderful models of projects that are brought in that have sufficient IP – intellectual property – protection of the ideas brought in that could be moved Fast Forward by a partnership with pharmaceutical and the National Multiple Sclerosis Society. So there are targeted areas, but of course it’s going to be very more modest in general funding overall for the average investigator, whereas the more traditional governmental and private foundations are going to be our primary sources.

MSDF

How do you account for the drop-off in pharmaceutical company funding?

Dr. Carson

Well, I am not an expert in economics, in the costs that it takes to take something to market, but I would speculate that it has to do with the difficulty of getting drugs that work in the brain that pass all the various measures of blood-brain barrier, unexpected toxicities and side effects. And so I think this area of pharmaceuticals has had great expense but great dropouts. So for great expense there hasn’t been a lot of drugs coming out except in targeted areas. I would say recently it’s been very exciting about the therapies that are coming out in MS research.

MSDF

So do these three sources – government, nonprofit, for-profit – do they tend to support different types of research?

Dr. Carson

Yes, very much so. I think as we very much know, you go to NIH, it’s a good scientific idea, needs to impact health, could be a basic science issue that applies to MS but also might apply to Alzheimer’s diseases, neural inflammation, or a variety of other diseases in childhood. When you get to a private foundation, the private foundation has taken donations or raised money very specifically for a disease, and so different private foundations are going to be focused on how much other research is applied to the disease, but also how translational it is. How important that translational element is going to be specific to the different foundation. But all of the private foundations are going to be very specific that this is not just a good idea, but is a good idea for their diseases, specifically multiple sclerosis.

MSDF

So let’s say you are a researcher, possibly a young researcher, searching for his or her first research funding. How do you strategize the search for research funding?

Dr. Carson

Very good question. I don’t think there’s one right answer to this and one has to look at one’s own portfolio of research, one’s resources, and what one can actually deliver after one has made a promise in a grant proposal. And I think you need to as a young researcher get advice from senior researchers and investigators in your area in your field to see how to go forward. But very often the best way is to take advantage of the pilot grants, the junior investigative grants that are really targeted to getting you off the ground and can have ideas that are high-risk, high-impact.

There are also many of these pilot grants from the private foundations, such as the National Multiple Sclerosis Society has a pilot project; it’s aimed at getting folks to get their early funding in MS to sort of capture them as a long-term MS researcher. So I think the pilot grants are a good way to start to get that bolus of research-funded publications, demonstrate your productivity level so that you get the larger grants from NIH.

MSDF

So let’s talk specifically about the National MS Society and Erase MS, which are the two large nonprofits that you’ve been involved with. How do their funding philosophies differ?

Dr. Carson

Well, I’m not really ready at this point to talk quite about more about the Erase MS, because I’ve just joined their scientific advisory board and I am about to start participating in their review cycles. And so I think it’s best to go through that cycle a few more times before commenting on that. But I would say it’s going to be very focused. They are also looking at bringing together research centers, and the Erase MS is very much focused on therapies and things that are going to move things forward quite fast. So in that sense, the MS Society is a more longstanding society; it has been on my mind one of the best models of collecting money, giving out money to researchers, making sure the research is very specific to MS. And this goes back to my prior point. Having been on MS study sections, it’s very important for them – this can’t be just a good idea – it has to be applying to MS.

So one of the things I think is the other very big difference between these is the MS Society also has a lot of different types of grant funding programs – these pilots which I just mentioned; training grants; transition grants which are very important to the junior investigator which will take you being from a senior post-doc to an independent position; as well as larger grants, 3-year grants, that are sufficient to carry a major project.

MSDF

So there’s a perception in the public, I think among scientists as well, that some of the big disease societies spend 90% of their funding on administration and 10% on funding research. How does the National MS Society stack up in that regard?

Dr. Carson

I would say the MS Society is a model of what most disease societies should be. I have been impressed by them from when I entered the research field starting off in MS and being funded – so just for conflict of interest, I was funded at 5M as a post-doctoral fellow – and what I have been impressed because I have had colleagues, I have had neighbors who develop MS or children who have MS, so I’ve seen it from both sides. I am very impressed how they keep a very lean, mean administration, they keep reinvestigating how they should be distributing the money.

They think about how much of the money is really going toward patient causes, as things about wheelchairs and thinking about those things, but also in the research; what’s the right time and how much to give the pilots to just generate these, you know, high-risk but potentially high-impact projects and keeping the money small. They look at things for these transition awards to really capture people when they saw that this was a dropout period that people were trying to have a problem launching. They are the ones when you are trying to get that NIH grant and you’ve been a successful investigator, they are focused on MS and they get these nice, shorter three-year grants. And they are very focused. And sometimes if you’re thinking it may be a little too harsh, but saying that it’s MS-focused.

So if you are somebody who’s a donor, you should be very happy with the money that you’re giving. And they’re constantly reevaluating the distribution of the dollars, the impact, and, hence, they came up with the Fast Forward. How do they facilitate the problem of pharmaceuticals not bringing enough drugs to therapies, how could they aid this process? Hence, fast forward; trying to bring in nice grants, innovative grants, linking them up with pharmaceuticals to move things forward. So, in a nutshell, they are very milestone oriented not to keep being their own operation alive, but they can’t cure MS to make your life with MS as palliative. You have as much retention of your motor and other capabilities and that you can arrest disease process and perhaps reverse it. So they are very milestone oriented, and I’ve had high respect for how they keep re-self-examining the organization.

MSDF

Well, I’ve come to the end of my prepared questions. Is there anything that I haven’t asked about MS research funding that I should have asked, or anything you’d like to add?

Dr. Carson

I wouldn’t be afraid of entering the field because of the funding. I think there are multiple ways to have funding. And sometimes you won’t go through the traditional MS societies, sometimes it’ll just be a great idea and you’ll find some other kind of innovative idea. And the last thing I would say that you haven’t asked is that we’re past the time of being the lone-wolf researcher; it really is time to come together, as we have at the symposium here, is taking diverse experts, coming together and melding together projects. These are the ones that are going to be the most competitive in a sense, not only of getting funding, but if we’re really looking at curing diseases, are the most likely to stand the test of time with the diversity of opinions and eyes looking at the problem.

MSDF

Dr. Carson, thank you very much.

Dr. Carson

Thank you.

[transition music]

Thank you for listening to Episode Twenty-Nine of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the non-profit Accelerated Cure for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is vice president of scientific operations.

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

 [outro music]

[intro music]

Hello, and welcome to Episode Twenty-Eight of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.

This week’s podcast features part two of an interview with Dr. Brenda Banwell in which we discuss pediatric MS. But to begin, here’s a brief summary of some of the latest developments on the MS Discovery Forum at msdiscovery.org.

Researchers recently put a simple measure of corpus callosum atrophy to the test in a 17-year-long study. The team measured the area of this inter-hemisphere highway in MS patients and found it correlated with their cognitive and physical disabilities over time. Corpus callosum area is faster, easier, and cheaper to measure than volume, since it requires no special equipment beyond the typical MRI machine. The researchers hope they will be able to demonstrate that this measurement can also predict disease course in future studies with larger cohorts.

Every Friday we curate research articles on all topics related to multiple sclerosis and highlight our favorites in the “Editors’ Pick.” Two weeks ago, the editors’ picks included a study on the HPV vaccine and MS and another about how cinnamon can ameliorate EAE. Last week we chose a study on heterogeneity among oligodendrocyte precursor cells and another on teasing out the causal variants in genetics association studies. You can see our weekly picks by going to our website, clicking on the “Papers” tab, and selecting “Editors’ Picks.” In addition to the Editors’ Picks, we link to every MS-related study found in PubMed.

Our senior science writer, Carol Morton, will be at the Keystone meeting on Neuroinflammation in Diseases of the Central Nervous System in Taos, New Mexico from January 25th through the 30th. She will be on the hunt for good stories and interviews for this podcast, so be sure to say “hi” and tell her all about your latest work.

[transition music]

Now to the interview. Dr. Brenda Banwell is Professor of Neurology and Pediatrics at the Perelman School of Medicine at the University of Pennsylvania and chief of the Division of Neurology at The Children’s Hospital of Philadelphia. Last week, we talked about a new journal called Multiple Sclerosis and Related Disorders, of which she is one of the co-editors-in-chief. This week we turn to her particular subspecialty.

[Interview]

Interviewer – Dan Keller

I’m here at The Children’s Hospital of Philadelphia with Dr. Banwell, and someone from the public affairs office is here with us. Dr. Banwell, let’s talk about pediatric MS. What are some of the clinical features that you see that may distinguish it from adult?

Interviewee – Brenda Banwell

Maybe walk you through a little bit of the journey that the pediatric multiple sclerosis field has taken over the last 10-12 years. When pediatric multiple sclerosis clinics were first being created which was in the late 1990s, the literature on pediatric multiple sclerosis was extremely brief; it was a mixture of patients that we now recognize have multiple sclerosis, some have what we call acute disseminated encephalomyelitis – ADEM – and still others had different demyelinating disorders. And there were no consensus criteria for the diagnosis of multiple sclerosis in children and the criteria for the diagnosis in adults did not include pediatric-onset patients formally. All of that has changed. And in the process of making the diagnosis of multiple sclerosis more clearly, we obviously had to look at the clinical features.

So, first of all, I would say that multiple sclerosis onset during childhood and teenage years is relapsing-remitting in character, so clear relapses and periods of clear remission. We have not seen children with primary progressive multiple sclerosis. Worldwide there are a very, very small number of children who may have that diagnosis; it’s extremely unlikely that there are very many, so for all intents and purposes it’s a relapsing-remitting disease during the pediatric age group.

The clinical features of attacks are generally very similar to adults with a few caveats. In children who are under about 10, there’s a likelihood that the children will present a little more atypically than adults. The younger children present with an episode with multiple neurological deficits, confusion, even impairment in level of consciousness which can make that first episode very difficult to distinguish from the more traditional acute disseminated encephalomyelitis, the important difference between the two being acute disseminated encephalomyelitis is a monophasic disease, so one attack almost always without any MRI evidence of new disease over time and no further clinical relapses in the vast majority of those children. So it’s a very important diagnosis to distinguish from the lifelong disease, multiple sclerosis, and one can distinguish them obviously on the basis of time but also on certain MRI features. And specifically when one looks at the first presentation, looking for risk determinants for multiple sclerosis are also important.

So in that vein, we’ve looked at things that are associated with the likelihood that a first attack is really multiple sclerosis, and those include prior exposure to Epstein-Barr virus, which gives one about a sixfold increased likelihood of having MS; low vitamin D levels which is a problem because low vitamin D levels are quite common in the community now across the board in certain parts of the world, but children who have very low levels are more likely to have multiple sclerosis compared to children whose vitamin D levels were higher when they present with an acute event.

If the MRI scan in the brain shows areas of what we call “T1 hypointensity”, which are black holes or really are indications of focal prior brain injury, then those patients are much more likely to have multiple sclerosis. And the reason for that is that in multiple sclerosis, the first attack when you first have the deficits, there’s likely been a period of time behind the scenes where the immune system has begun to attack and has had focal areas of injury that the patient didn’t recognize but are clearly visible on MRI, so MRI is our extraordinarily helpful guide. So areas of abnormality in the brain that are in the what we call periventricular white matter, and then these dark areas on these what are called T1 sequences are strongly indicative that this is a first attack of multiple sclerosis.

Conversely, most children with transient illness either have a normal brain MRI and maybe have inflammation in the back of the eye, the optic nerve, or the spinal cord, or they have this ADEM – acute disseminated encephalomyelitis picture – which gives you these hazy, widespread, large, ill-defined changes in the brain MRI that are at least visually quite different from multiple sclerosis. The key subsequent to that is that in patients with multiple sclerosis, by definition there will be new disease over time both on serial MRI scans and clinically. And that is also the case in young adults with relapsing-remitting multiple sclerosis.

Genetically, pediatric MS patients do have – at least those from northern European heritage – a higher likelihood of having what we call the HLA-DRB*1501 locus, which is a gene that is important in immune system development or at least immune system recognition of self. And that relationship is true in adult-onset MS as well, and over the last few years the number of genes that have been linked to multiple sclerosis risk overall, and that panel of genes is similar in pediatric-onset MS.

So I think the overall message is that relapsing-remitting multiple sclerosis in children and adults is very likely to be the same disease. There are some subtle differences relating to the age of the patient, but if you follow people over time the relapsing-remitting character and the changes on imaging and these clinical feature of kids are really quite similar to relapsing-remitting MS in young adults.

MSDF

When you mentioned exposure to Epstein-Barr virus as a risk factor, if you looked at adults about 90% of people have antibody. Do kids generally not have such a proportion of antibody and it’s more indicative there? Does it tell you more if they are positive than in an adult?

Dr. Banwell

There’s a lot of evidence that suggests that your multiple sclerosis risk is determined by where you grow up in your childhood years. You may not manifest with the disease until you’re 20 or 30, but all sort of studies, particularly immigration studies, strongly suggest it’s where you grow up that determines your risk. Therefore, if something is a risk factor, one ought to have it if your onset is a 6-year-old or an 8-year-old or a 10-year-old, if it’s important in causing the disease. So when we looked at Epstein-Barr virus exposure in pediatric-onset MS patients, about 80-85% are positive, which compares to only about 35-40% of regional, age, and sex-matched healthy children. So our power to make the relationship is very high. What the Epstein-Barr virus means to the person may be very similar in kids and adults. Certainly in adult-onset MS patients, about 97-98% are positive, which compares to about 90% of the healthy population. So it’s still higher but, of course, you’re sampling the adult patients way past when the exposure may have occurred, and so there’s been time for people who don’t have the disease to also experience the exposure, it just doesn’t matter – presumably – to them; they’re not manifesting with MS.

In children, though, when we’re looking at patients who are presenting very, very close to when they presumably had the key risk exposure. So we think that’s biologically important. We’ve also looked at viral shedding. So Epstein-Barr virus is an interesting infection because once you acquire it, it lives in your B-cell population so you have EBV-infected B cells, and about 20% of the year you shed the virus in saliva, which is why it’s so easily spread, particularly in adolescence, which is when it’s particularly acquired. So we looked in our pediatric MS patients at how many times in the course of a year, so with a sample done with most swabs once a month, were they shedding the virus, and looked at Epstein-Barr virus-exposed healthy kids. Healthy children shed the virus 20% of the year, as has been previously reported; MS patients, it was 66-70% of the year.

So one of our hypotheses that we’re currently exploring further is whether maybe part of what Epstein-Barr virus might do in MS is, first of all, shed more often so you’re controlling it less well. Every time you shed the virus, your immune system has to turn itself back on and put the virus back into its latent state. If you don’t you can end up with all sorts of complications including lymphoma. And so if part of Epstein-Barr virus’ role in MS is turning the immune system on multiple months per year, that isn’t probably what you want when you have an autoimmune disease; you don’t want your immune system being turned on multiple times a year, particularly if unfortunately you turn on a component of the immune system that may then be directed at the brain. So that’s an interesting phenomenon that we’re currently doing further research on.

MSDF

So it sounds like the EBV is something of a polyclonal activator of B cells which then cross-react in the brain, or do react in the brain?

Dr. Banwell

Well, that’s the next stage is to see if you look at what immune cells are responding to the challenge of this reactivated EBV, is it that there are specific T-cell clones, and if so are those T-cells specifically looking at proteins expressed both by EBV and by proteins in the central nervous system, sort of a molecular mimicry model, which might be true? Or is it just unfortunate that you’ve turned the whole immune system on, or a large number of aspects of the immune system on, which is more of a general immune process? We don’t know the answer to that.

MSDF

Considering these patients start out with relapsing-remitting MS earlier, do they progress to secondary-progressive earlier or at the same age as someone who gets it as an adult?

Dr. Banwell

Good question. So the only really good paper on that question, keeping in mind that if we go from prospective studies that are really only started in 1999 to 2000, we don’t have a lot of prospectively rigorously studied pediatric patients. But Dr. Renaud in the New England Journal of Medicine published a paper from the French database where they looked at patients who reported pediatric-onset MS. And what they found was that from first attack until the point at which 50% of their pediatric-onset patients had started into secondary disease progression, that time interval was about 20 years, which is about 10 years longer than one would report on average in adult-onset MS. So if you look at adult-onset MS patients, 50% of them will have entered into secondary disease progression after 10 years from first attack. This is all untreated patients, which of course now is no longer really much the case in developed parts of the world.

So the patients with pediatric-onset take longer to start into secondary disease progression, but if you’re only 6 or 7 or 8 when you have your first attack, you’re 28 when you start to develop disability, which is about 10 years younger than most of the adult-onset patients. So the take-home message is it is certainly not more benign based on this particular data, the age at which patients are at-risk of becoming disabled is actually younger, but the time interval from the beginning of their disease until that time point is longer. And we hope that the current therapies and the new emerging therapies will change that outcome, but of course we only are just beginning to have a chance to see that.

MSDF

What are some of the challenges in doing clinical trials with a pediatric population?

Dr. Banwell

So in adult-onset MS patients, the clinical trial models have been very large; they’ve been randomized, double-blind, placebo-controlled, rigorously done studies that have often employed 200-400 individuals per study arm. And that is often quite feasible because the large MS programs around in North America and in many parts of Europe, an average adult MS clinic where MS is a common can have 3,000 patients alone. There are probably fewer than 3,000 pediatric-onset MS patients available for clinical trials worldwide total, and even that number may be inaccurate. So most pediatric MS programs in the world, of which there are still relatively few that have anything more than five or six patients, are really, really few and far between. So there just simply is a markedly reduced number of pediatric MS patients available for clinical trials.

Also challenging the current environment is that there are multiple trials all coming forward at the same time. So the FDA and the European’s Medicine Agency in particular require what they call “Pediatric Investigation Plans” – or PIPs – for all new drugs that are coming to market. In the MS field there are multiple new drugs coming to market. All of them have filed these Pediatric Investigation Plans. So even if we had the number of patients to power one study, we certainly don’t have enough patients to power five or six concurrently, therefore we run the risk of a given trial failing because it doesn’t reach its enrollment numbers.

We have families facing choices between multiple potential clinical trials at the same time and centers facing the challenge of launching multiple trials at the same time and the inherent difficulty with all of the work that goes into getting a study up and running at a given center. Pediatric MS patients have never previously been offered pediatric trial opportunities, so the culture of being in a trial is new so it’s a learning curve for everyone. And the medications that are being put forward have varying priorities. So some of the medications are oral, which may be quite appealing to children who are not, understandably, very keen on injections; some are given by infusion and that has varying challenges.

A clinical trial is not just an enormous time commitment on the behalf of the patient, in which our case is a child, but also their parents who have work and other commitments and other children. So being part of a clinical trial is an enormous commitment for a family, which is different than the commitment experienced by an individual who’s making that decision on their own behalf. And then adding to all of those challenges is the safety aspects of all these new medications, and of course our top priority amongst anything else is to make sure that our patients stay safe.

And so where there may be marked similarity in relapsing-remitting MS as a disease between children and adults, these therapies are being administered at a different time in terms of brain maturation, to a lesser worry but still important in terms of different levels of immune maturation, and certainly – very importantly – at a different stage of life in terms of acquisition of infection. And so many of the new medications that are coming online are more powerful than the medicines that are currently available, many are more capable of suppressing immune responses which puts a significant burden on making sure that everybody is fully vaccinated to the various things we can vaccinate against, but still kids are going to acquire their first infections during the window of time they may be on some of these medications. And so it’s really quite similar to some extent to some of the pediatric oncology care plans that we have to be very, very aware of.

MSDF

It looks like the Canadian database of pediatric MS patients is one of the largest; I think when I talked to Amit Bar-Or, it was about 420 or 450. It sounds like there’s a real vying here for patients in terms of clinical trials, and is it even feasible; is it something that you should just discuss with the FDA and say how is this possible to do?

Dr. Banwell

So I am one of four members of a clinical trials advisory group on behalf of the International Pediatric Multiple Sclerosis Study Group, which is an international group of about 150 physicians from 40 countries, so I do serve on an advisory to FDA and EMA under that umbrella. And the group of us have very much expressed this concern to FDA and EMA and have articulated our worry about underpowered trials. It’s a difficult environment, there’s a lot of discussion still to be had. The general statement from the regulatory authorities for each of the individual medications that are coming forward is that they are required to have a pediatric plan. And that was a hard-fought battle over many years to try to increase high-quality evidence for treatment of children, which all of us who treat children endorse.

So it’s not that we don’t want there to be good trials, it’s just, unfortunately, the reality is that it’s going to be very difficult to do traditional study designs with large arms and placebo-controlled, randomized, double-blinded models are not always going to be suited for all of the therapies. They’re not possible to do for every therapy that’s coming forward, and there’s going to need to be some discussion at a minimum on trial design and potentially on which trials are being done in what order, although that, of course, is certainly not my purview to decide, but it isn’t feasible to run multiple trials in this rare disease at the same time. So we’re going to need to look at rare disease models of therapy that have been put forward for perhaps some of the rare childhood cancers, for example, and other diseases, and we’re going to need the regulatory authorities to recognize we can’t use adult MS study designs for pediatric MS patients.

MSDF

Very good, I appreciate it. Thank you.

Dr. Banwell

Oh, you’re welcome.

[transition music]

Thank you for listening to Episode Twenty-Eight of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the non-profit Accelerated Cure for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is vice president of scientific operations.

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

 [outro music]

[intro music]

Hello, and welcome to Episode Twenty-Seven of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.

This week’s podcast features an interview with Dr. Brenda Banwell about a new journal on multiple sclerosis and related disorders, of which she is a co-editor-in-chief. But to begin, here’s a brief summary of some of the latest developments on the MS Discovery Forum at msdiscovery.org.

This week we published two stories related to articles published in the December 2014 issue of JAMA Neurology. The first article is about the interim results of the Halt MS trial. In this phase 2 clinical trial, physicians performed autologous hematopoietic stem cell transplants on 24 patients with relapsing-remitting MS. In other words, the team obliterated the patients’ existing immune systems and attempted to hit the reset button by infusing the patients’ own stem cells. Three years after the treatment, 78% of patients showed no signs of disease activity, significantly higher than similar studies using conventional MS treatments. However, not everyone is popping the champagne yet. Some are concerned that the treatment may not have been aggressive enough to eradicate the patients’ entire immune systems, and it will be only a matter of time before some patients start showing signs of disease activity once more. Others are concerned that the treatment was unnecessarily intense and risky, suggesting safer methods of stem cell transplant would be effective in resetting the immune system.

Halt MS is one of the trials using a new primary outcome measure called “no evidence of disease activity” or NEDA for short. NEDA is basically a fancy way of saying “remission”; that is, no relapses, no disability progression, andno new lesions on MRI. NEDA sets a new treatment standard for patients and their doctors, reflecting the hope of a new generation of disease-modifying therapies.

But is NEDA really a feasible clinical care target? Our second story this week takes a look at this issue with the first real-world cohort study. Researchers asked how many people with relapsing-remitting MS maintained NEDA status seven years after diagnosis. While that goal remained elusive for all but 8% of patients, NEDA status at two years was highly predictive of no disease progression at seven years. Many questions remain about NEDA. But in an editorial accompanying the study, researchers suggest that NEDA is still a worthy, albeit very ambitious, goal.

What do you think? Let us know on the discussion forums at msdiscovery.org/forums/discussion.

[transition music]

Now to the interview. Dr. Brenda Banwell is Professor of Neurology and Pediatrics at the Perelman School of Medicine of the University of Pennsylvania and is chief of the Division of Neurology at The Children’s Hospital of Philadelphia. We met to talk about a fairly new journal called Multiple Sclerosis and Related Disorders, of which she is one of the co-editors-in-chief.

[Interview]

Interviewer – Dan Keller

I’m here at The Children’s Hospital of Philadelphia with Dr. Banwell, and someone from the public affairs office is here with us. I’m just wondering why did you see a need for a new journal?

Interviewee – Brenda Banwell

At the time that we launched Multiple Sclerosis and Related Disorders, there were journals focused solely on multiple sclerosis and journals on neurology broadly, but not one that focused specifically on multiple sclerosis and the various and increasing number of demyelinating disorders of the central nervous system that are being recognized. So Multiple Sclerosis and Related Disorders was meant to be a home for sometimes comparisons, sometimes new insights, and certainly thoughtful reflection on the scope and breadth of demyelinating disorders in the central nervous system in adults and in children.

MSDF

Is there a certain amount of waiting, or it’s just the volume of papers that you get in that determines the mix between multiple sclerosis and other demyelinating disorders?

Dr. Banwell

Really it’s actually the quality of the papers we receive that drive the selection into the journal. To date, we have been blessed to receive some very interesting manuscripts, some of which relate to multiple sclerosis but many others relate to neuromyelitis optica, which is one of the disorders we were interested in; in antibody-associated encephalopathies; in patient perceptions of demyelinating disease, which is from the area that I think is very interesting and relevant; and then even some basic science, manuscripts that have looked at mechanisms of the immune system targeting the central nervous system.

MSDF

Is there a particular editorial philosophy?

Dr. Banwell

I guess the one my co-editors and I would say that we’re looking for manuscripts that push the envelope a little bit in terms of hypothesis generation. We like to see a thoughtful reflection on where the next step needs to be in the papers that we accept. And we’re not at all uncomfortable with being a little bit provocative in terms of perhaps people broaching new hypotheses as long as those hypotheses are well defended and can generate the next step of research.

MSDF

So it sounds like you’re also delving into basic science, or at least early clinical studies here, too?

Dr. Banwell

We’ll delve into it. We are not a basic science journal, so we would not pretend to be Cell or Natureor any of those sorts of journals. But certainly many of the manuscripts that we’ve accepted have discussed potential hypotheses based on basic science research and how that might tie to the clinical picture.

MSDF

One question that always arises with a new journal is why should people want to publish in this journal as opposed to some of the more established ones?

Dr. Banwell

Well, I think like any new journal, we have a lot of opportunity to accept manuscripts. We have very quickly gotten to the point where we have a very high caliber of manuscripts, which I think speaks to the interest in the field, so the journals that are arguably in competition with us are also now increasingly receiving high quality manuscripts as well. And I think overall it reminds us that there is actually quite a bit of research going on in multiple sclerosis and related disorders, and therefore there’s room for several journals in the field at this time.

MSDF

Is it now being indexed in PubMed?

Dr. Banwell

We have applied for indexing and we’ll hope to hear very shortly.

MSDF

Is there any problem or have you faced any barriers?

Dr. Banwell

No barriers. It’s just that you have to have a certain number of manuscripts published, you have to show that the manuscripts are of high quality, and you have to have been in the field long enough to actually have enough publications for them to judge the quality of what we’re doing.

MSDF

I see that you have co-editors-in-chief. Who are your colleagues in this?

Dr. Banwell

So there’s Dr. Chris Hawkes and Dr. Gavin Giovannoni from England, and Dr. Fred Lublin from the United States.

MSDF

Anything else important to add about the new journal or the things that it’s come out with lately?

Dr. Banwell

Well, we have a lay review author as well, and we do hope to increase some scholarly input from the lay public over time. Certainly we’re interested in maintaining the sort of price we put on novelty and in encouraging people to submit work that is perhaps looking at a new angle in the field. I think the related disorders aspect of our journal is an important component, both of the title and also of the concept. We are particularly interested in some of the emerging disorders that we now realize are potentially, if not multiple sclerosis, certainly in the field of immune-directed responses in the central nervous system. So I think that aspect of our journal speaks to an area of the field that might not have been previously quite so well captured in the existing journals.

MSDF

Does this journal lend itself to a more global approach to demyelinating diseases, since it’s multiple sclerosis and related disorders as opposed to just looking at MS as an isolated condition?

Dr. Banwell

Certainly in concept, yes. I think in fairness to the other journals that I think are all excellent and also in the field, we are not the only ones that are broadening the scope. And I think that speaks to the discoveries. So with the identification in 2004 of the aquaporin-4 antibody, and then subsequent to that really compelling evidence that the aquaporin-4 neuromyelitis optica story broadened and recognized a very specific subgroup of patients, that is also happening with other antibodies potentially, and there’s some emerging information about, for example, NMDA receptor encephalitis and other disorders that weren’t really recognized as such a few years ago. Our journal is prioritizing this type of sort of patient base and diagnostic categories, but so too are other journals that are also excellent in the field. So I think in fairness, everyone is recognizing that there’s more to the story.

MSDF

Is the NMDA antibody story with the catatonia?

Dr. Banwell

So NMDA receptor encephalitis is a disorder actually discovered by Josep Dalmau at Penn, so very near and dear to our heart here. The patients present sometimes with psychotic features, they can become quite catatonic. There’s been some lay publications on that. “Brain on Fire” was a book written by a survivor of NMDA receptor encephalitis. In children we certainly see – and in adults, but certainly in children – we see a number of patients present with severe seizures and then with abnormalities of movement. When these patients present they can be catastrophically ill, often in intensive care unit. Over time as the patients recover, miraculously it seems because it really does appear to be quite miraculous, the patients can have a full recovery. So it is a disorder that’s extremely important to recognize and can be misdiagnosed quite easily as an infectious encephalitis, as initially other psychiatric disorders, and in some patients as a really severe form of epilepsy, all of which it is, but it has a better overarching diagnosis. And making the diagnosis certainly gives hope in terms of long-term prognosis, and we do use specific therapies for the patients with the diagnosis.

MSDF

Very good, I appreciate it. Thanks.

Dr. Banwell

My pleasure.

[transition music]

Thank you for listening to Episode Twenty-Seven of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is vice president of scientific operations.

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

 [outro music]

[intro music]

Host – Dan Keller

Hello, happy new year, and welcome to Episode Twenty-Six of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.

This week’s podcast features an interview with Tim Kennedy about remyelination and neural development. But to begin, here is a brief summary of some of the latest developments on the MS Discovery Forum at msdiscovery.org.

According to a new clinical trial, azathioprine, or AZA, may be as effective as interferon beta. The generic immunosuppressant was effective in both reducing relapses and reducing new brain lesions in the multicenter trial. This may not be surprising since the drug has been used off-label to treat MS for several decades. If trials continue to go well, AZA may become the go-to alternative for patients who can’t afford brand name interferons.

A pair of Canadian studies recently showed that both neurodegeneration and inflammation may start in the early stages of pediatric multiple sclerosis. One team found epitope spreading in the blood of children shortly after the onset of MS, suggesting a potential new diagnostic tool. Though children comprise only 2 to 10 percent of the MS population, data gleaned from them may provide insights into the disease as a whole.

If you enjoyed our end-of-the-year interview with Alan Alda and find MSDF to be helpful, please consider supporting us with a donation. We share Mr. Alda’s philosophy that closing the gaps between scientific disciplines is key to improving scientific progress. To make a donation, visit msdiscovery.org and click on the green “Support MSDF” button next to “Research Resources”.

[transition music]

Now to the interview. Tim Kennedy is a researcher at the Montreal Neurological Institute. He met with MSDF to talk about the role of certain molecules and receptors necessary for oligodendrocyte development, maintenance, and function and their implications for remyelination.

Interviewer – Dan Keller

Welcome, Dr. Kennedy. Let's talk about the life of oligodendrocytes. These are important for myelination and probably play a role in remyelination. What is the life of an oligodendrocyte? How does it start out? And what does it react to?

Interviewee – Tim Kennedy

Many labs around the world have been studying the life history of an oligodendrocyte and also the lineage of the cells and how they differentiate during normal development. One of the reasons for doing this is that oligodendrocyte precursor cells are present in the mature nervous system and almost certainly contribute to remyelination in demyelinating diseases like MS. Oligodendrocyte precursors are born in the early embryonic CNS, and from the very restricted regions where they're born they then migrate away to populate all of the regions of the mature CNS where myelin occurs. In the lab here, we've been very interested in the molecular cues that direct and influence oligodendrocyte precursor migration. These include a family of proteins called netrins that we work on. And receptors for netrin like a protein called DCC. DCC stands for deleted in colorectal cancer. It was originally identified in cancer, and we now know that it has a critical role in the central nervous system in the migration, maturation, and maintenance of myelin by mature oligodendrocytes.

MSDF

Some of these molecules take on different functions as the oligodendrocytes mature. How do they react, or what do these molecules do over time?

Dr. Kennedy

When an oligodendrocyte precursor is born, it makes the netrin receptor DCC, but it doesn't make netrin. What the cell does is it responds to netrin in the environment, and through DCC reacts to it, and the netrin directs the cells to migrate. It tells them to initially migrate away from the position where they're born and sends them in the direction of axon tracks that require myelination. In mature myelinating oligodendrocytes, one of the huge surprises we had is that both of these proteins are made. Now, both netrin and DCC are required for normal neural development. If we examine a conventional knockout mouse that lacks either netrin-1 or DCC, those mice die within a few hours of being born, and there's a massive disorganization of the nervous system. So these are essential for normal neural development. When we look at the mature nervous system, we see that every single oligodendrocyte, every single mature myelination oligodendrocyte, makes readily detectable levels of netrin-1 and also the receptor for netrin-1, DCC. And a very simple statement of the question that we wanted to answer is what's the point of that? Why do these cells make these proteins that are essential for normal neural development but make them in the adult nervous system? In every adult human that we encounter, every single person, we're making netrin-1 and DCC in our brains right now. So what's the point? One of the functions that we've recently identified is that DCC produced by oligodendrocytes is required for the maintenance of myelin. Now what that means is that initially when we looked at the distribution of netrin-1 and DCC in relation to myelin we see that they're enriched at paranodal junctions. Paranodes are at the ends of internodes that are the regions of compact myelin that wrap and insulate an axon. The paranodes are a specialization that's made by the oligo that then connects it and ties it down to the surface of the axon. The paranodes flank the node of Ranvier, which is the key point, the specialized region along an axon that regenerates the action potential. So if we think of the internode of compact myelin as the region where the oligodendrocyte insulates the axon and allows the action potential to jump from node to node, the paranodes are the specializations at the end that tie it down. Now, the paranode is where we see the netrin and DCC enriched. If we take away either netrin-1 or DCC from oligodendrocytes, what we see is that the paranodes begin to come apart. Now in a very recent publication, what we did was use a genetic trick called cre-lox recombination to selectively take DCC out of mature myelinating oligodendrocytes. In these mice, the mice develop perfectly normally, the nervous system develops normally, the myelin develops normally. But then, at two months of age, we induce the deletion of DCC only from oligodendrocytes. Now having taken DCC out of oligodendrocytes, what we see is that first the paranodal junctions start to come apart, and then as we let the mice age the compact myelin itself starts to become disorganized. Now, that's interesting because what we're able to document in these mice is a progressive disorganization of the myelin produced by the oligodendrocyte. The progression is interesting, obviously, because we believe that this has identified a new mechanism that maintains myelin, and we would then relate that to the progression of demyelinating disorders like multiple sclerosis. A consequence of having lost DCC is that the action potential conduction velocity in the nervous system is delayed, and when we look at the mice themselves – and look at their behavior, put them through behavioral tests – what we see is that they become uncoordinated and slower in their movements. So again, this would all be consistent with this disruption of the myelin along the axons in the central nervous system due to the loss of DCC. And it's an indication that DCC being made by oligodendrocytes is absolutely essential to maintain the appropriate organization of myelin.

MSDF

That explains why myelin may become disorganized. Now, if there is a state in which it's already disorganized, which we look at someone with MS, is there any indication here how to remyelinate knowing what you now know about what's required for maintenance of myelin?

Dr. Kennedy

Certainly. What's really exciting having found that DCC is essential to maintain myelin is that this is a new biochemical mechanism that is required to organize and maintain the structural paranodal junctions, and that that's critical for the integrity and the maintenance of compact myelin. Now, DCC is a transmembrane receptor, and every single component of the signal transduction pathway downstream of DCC is potentially a drug target that could be manipulated to enhance the maintenance of myelin. So this is a new biochemical mechanism that exists in oligodendrocytes that promotes myelin maintenance. And that has enormous potential for trying to encourage the persistence of myelin in demyelinating disease.

MSDF

What about remyelination? I think you've said oligodendrocytes are born to myelinate. What's stopping them?

Dr. Kennedy

If we go back to the oligodendrocyte precursor in early development, what our studies of the developing nervous demonstrated was that oligodendrocyte precursors are repelled by netrin-1. The normal function of netrin-1 in the early embryo is to drive oligodendrocyte precursors away from where they're born so that they can go out into the rest of the central nervous system, find axons that need to be myelinated and myelinate them. That indicates that in the early embryo netrin-1 is a repellent for these cells. Again, we recently reported that in human MS plaques netrin-1 is present in those plaques. Where that's likely coming from is from the wreckage of cells that have died in those plaques. So I had said that mature myelinating oligodendrocytes express netrin-1. When those cells die and when the myelin is lost, the debris from those cells remains behind and potentially even builds up in plaques. There are a number of inhibitors of oligodendrocyte precursor migration that we now know are present in human MS plaques. These include proteins like chondroitin sulfate proteoglycans, semaphorins, and now netrin. What that strongly suggests is that when oligodendrocyte precursors are migrating in the adult brain to sites of demyelination with the intention of remyelinating an axon that has been demyelinated these inhibitors will very likely prevent those cells from entering the plaque and doing what they were born to do, which is to remyelinate. A very exciting thing about MS research today is that we know that the brain contains stem cells that produce oligodendrocyte precursor cells that readily give birth to these cells. So all of us have oligodendrocyte precursor cells in our head. Those cells are born to myelinate. They will migrate towards plaques where demyelination has happened, and if they're allowed to enter the plaque find the axon that needs to be remyelinated. And if they can be encouraged to overcome whatever it is that is blocking them from remyelinating, potentially that aspect of MS remyelination could be encouraged to happen.

MSDF

Do you have some ideas on how to overcome this blockage either clearing away the debris or making the oligodendrocytes insensitive to the inhibitors and the debris?

Dr. Kennedy Both of those approaches would be very appropriate. So encouraging the nervous system to clear away the debris we would predict that that would encourage remyelination to happen. In addition, although I said there were multiple inhibitors present in MS plaques – and those inhibitors have different receptors – downstream of those receptors it's very likely that common signal transduction mechanisms are engaged. So targeting those common signal transduction mechanisms inside the migrating oligodendrocyte precursor cell could very potentially nullify all of the inhibitors at once. If it was possible to turn off the sensitivity to those inhibitors, then we would predict that the cells would enter the plaque more readily, and more of the cells would then be able to encounter the axons that require remyelination, and we would obviously predict that that would promote remyelination happening.

MSDF

What are some of the big questions now to look at, solve?

Dr. Kennedy

The oligodendrocyte is an absolutely fascinating cell type. It's a highly specialized cell type, critically clinically important. We still understand very little about these cells. The mechanisms that I've been talking about that regulate the maintenance of myelin, those have only very recently been discovered. And I think it's extremely exciting that this type of thing is being found in oligodendrocytes. But these are still very mysterious cell types. I think the more we understand about the cell biology of the oligo the more we'll be able to target pathways in the biochemistry of oligodendrocytes to try and promote things like myelin maintenance and the ability to remyelinate. Being able to do those things and essentially manipulate these cells in specific ways, we can then overcome specific clinical issues.

MSDF

Does this go beyond MS? Are there other conditions that it applies to?

Dr. Kennedy

I think there are two things built into that question. One is that there are many diseases for which the cause either isn't clear – and MS would be in that category – or there are also diseases that have many different causes, but they may manifest in similar ways. So by understanding oligodendrocytes and being able to encourage oligodendrocytes to remyelinate, that could have broad applicability for treating the symptoms of many different forms of demyelinating disease irrespective of the cause of those diseases. Beyond that, as we come to better understand how cells move in the nervous system, how they migrate, how they form attachments, how they connect to each other, and how they maintain those connections, those kinds of insights are going to have broad applicability for all sorts of neurodegenerative diseases where the basic problem in the neurodegenerative disease is that the networks that are the nervous system are coming apart. And if we can encourage those networks to just stay together or rebuild themselves, then I think that again has broad applicability to many types of neurodegenerative diseases in the myelinating field and outside of myelination, as well.

MSDF

It sounds like it may even have applicability to not only neurodegeneration but in development where you may have miswiring such as potentially an autism or something like that.

Dr. Kennedy

Yeah. An exciting thing is that a lot of the mechanisms that I'm thinking about and we're thinking about in the lab is that the insights that got us working on myelin, that brought us to work on myelin really came from neural development and better understanding neural development; the studies of neural development identified proteins and gene families that have very, very potent actions in the nervous system. When we then looked at expression, we saw that they were expressed in the mature CNS, and that brought forth a whole other group of questions related to the function of the normal adult nervous system and also the degeneration of the adult nervous system in neurodegenerative disease. The exciting thing about that is that as we understand the molecular biology of the central nervous system better that's going to be applicable to development, to normal function, to enhanced function, and also promoting function in degenerative conditions.

MSDF

I appreciate it. Thank you.

Dr. Kennedy

You're very welcome.

[transition music]

Thank you for listening to Episode Twenty-Five of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is vice president of scientific operations.

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

[outro music]

[intro music]

Hello, and welcome to Episode Twenty-Five of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.

This week’s podcast features a special interview with actor and science advocate, Alan Alda, whom you may remember as Hawkeye Pierce in M*A*S*H. But to begin, here’s a brief summary of some of the latest developments on the MS Discovery Forum at msdiscovery.org.

Positive thinking may lead to positive clinical outcomes, according to a new meta-analysis. The investigators found that interventions such as cognitive behavioral therapy helped patients deal with physical symptoms like fatigue and pain. They suggested that psychological well-being should be assessed and treated along with physical disability in people with MS. The researchers also called for studies that examined the connection between the psychological and the physical more directly.

Moving from the macro to the micro, we recently published an article about axonal transport. Axons rely on motor proteins to carry cargo across long tracks of microtubules in order to survive. A disruption in this process is associated with neurodegeneration. Recently a team of researchers discovered that axonal transport is disrupted in mice with EAE. In this animal model of MS, even normal-appearing axons failed to transport organelles as quickly or as effectively as healthy axons. But the researchers were able to reverse the process, suggesting a potential new therapeutic target for drug development.

[transition music]

Now to the interview. Alan Alda is an actor known for his television roles in M*A*S*Hand The West Wing. But he’s also a longtime advocate of science and scientific literacy and the founder of the Alan Alda Center for Communicating Science at Stony Brook University. He met with MSDF recently to talk about the art of good science communication.

[Interview]

Interviewer – Dan Keller

What, at this point, would you say are the one or two biggest pieces of advice you could give to any technical person or a scientist trying to get his point across to the general public?

Interviewee – Alan Alda

I think the most important thing to remember is that it’s not nearly so important to worry about what you have to say to the other person, as it is to think about how the other person is receiving what you have to say. We know this intellectually because everybody knows that you want to know your audience, everybody knows you want to start where the student is, you know, find out what they know and build on that, that kind of thing. We all know that.

But one of the things that I think that we’ve found at the Center for Communicating Science that I helped start is that you need to get in the habit of doing that; you need to really go through the experience of actually opening up to other people, getting their feedback, being able to read from the signals that they give you on their face and their body language – all the various signals you can get – whether or not they’re really paying attention and really following you. If you miss one of the crucial words I say at the beginning of a paragraph, the rest of the paragraph is dead; you’re spending most of your time trying to figure out what I’m talking about.

MSDF

As an example, say, in Scientific American Frontiers, you elicited great storytelling; I mean, I assume part of that was picking the right speakers, but how do you coax it out of them in an understandable way? I mean can you essentially guide people without saying, “Hey, come on, bring it down, bring it down.”?

Mr. Alda

I think Scientific American Frontiers worked as well as it did because in a way it was a rare thing – I hadn’t seen it done before and so maybe it has, but I hadn’t seen it – where you had a naïve person – ignorant, played by me – and I wasn’t acting. I made use of the natural fund of ignorance that I came in with. I didn’t aspire to an ignorance I didn’t possess, it was real; I really didn’t know what these people did in the laboratory, and I really did want to know what it was. And I wanted to understand it, so I badgered them until I understood it, and I didn’t pretend I understood it if I didn’t. That step where they actually had to come to terms with this person standing right next to them looking up in their faces where they had to actually make it clear to this one person, that changed them in some way, that brought out the human being in them. And they forgot about the camera, they forgot about the millions of people that they might have gone into lecture mode to explain this to. They were talking to one individual and that made a big difference, because they became much more human.

So, yeah, I think that we had people who were comfortable being in front of a camera, but regardless of how comfortable they were in making their language plain-spoken, they had to get even more so when they talked to me because I really, I just tugged at their coat until I understood it. And something happened between us, there was some kind of connection between us that was very watchable, very interesting. I think that helped draw other people in. After we did that, I really wondered if a scientist didn’t have this person dogging him or her to get the information out, but to get it out understandably, what would do it? How could they get accustomed to speaking as though they’re talking to another person who really wants to know? And that’s when it occurred to me that I bet we could teach them improvising and that would help them get more personal, and it has.

MSDF

To envision one person.

Mr. Alda

Well, when you improvise, at least the way we improvise with scientists, it’s not for the purpose of getting them to be comical, or to make things up on the spot, or to be clever. The whole thing is designed to get the scientists to be accustomed to observing the person they’re talking to, because you can’t play these improvising games unless you’re tuned into the other person in a very powerful way. Once they get used to that and when they turn and talk to an audience, they carry with them that same ability to talk to the people and not over their heads and not at them. They don’t spray information at them anymore, they actually engage the audience, and that’s a tremendous difference.

MSDF

Let me switch gears a little bit. I don’t know if you’ve ever noticed it, I’ve certainly noticed it, between different closely related scientific disciplines – I mean, I cover medicine mostly – and people in just very closely related things, there’s no cross-pollination. They’re surprised when they hear something that’s going on. Oh, you know, that could be applicable to me. And I think there’s even a lack of communication between the disciplines between scientists. They can certainly speak in the same jargon, but I don’t know if there’s a barrier or if they’re just so wrapped up in their own stuff.

Mr. Alda

It seems to be a really serious problem that scientists need more and more to collaborate across disciplines, and the problem is that they often – I think I could say often – don’t understand one another much better than a layperson understands a scientist in a specialized field. So at a certain level, at a certain distance from one another’s work, they’re really in the position of an interested layperson rather than a collaborator, rather than a colleague. And we have to bridge that gap if we’re going to get the benefits of collaboration. And I’ve heard some horror stories of scientists getting together and not understanding one another. And on the other hand, I’ve heard these really heartbreakingly wonderful stories.

When we have a workshop with a range of scientists, scientists from several different fields, one of the wonderful things they say is this has been great, I got to understand, I got to hear about this guy’s work and I never knew anything about it before. They’re hearing an explanation of another person’s work in terms that they might say it to the lay public. It’s acceptable to the other scientists because we don’t ask them to dumb it down, we ask them NOT to dumb it down just to make it clear. So they’re getting a clear version of somebody else’s work that doesn’t include the jargon of that specialized field. It’s stripped of its jargon, it’s spoken in plain language. And the emotion, the passion that the scientist feels about it is allowed to come out because that’s part of the human story that science is. Science, rather than being passionless, is generated by passion. So it’s great that that comes out in this work.

MSDF

In the training, obviously you can tell if there’s a difference between before and after. But have you ever been able to test the durability of this, that these people retaining these? Or do they lapse back? Or can you tell?

Mr. Alda

It’s hard to get measurements on the success of this, but we’re beginning to get some early results because we’ve been working with teaching assistants. And teaching assistants are graduate students who are asked to give courses to undergraduates to see if the undergraduates want to go into science. And one of the problems has been that a lot of them drop out because they can’t get interested in the science partly because the teaching assistants don’t have any training in communication or in education; they know the material but they’re not really experienced at communicating. So we put them through a course of communication, and then we find some of the numbers we’re getting back are that the students are rating them as highly or higher than people who have been doing this for five years, and these are first-time teaching assistants.

Next thing we’ll check on is are their grades getting better and other things you can measure. But so far, the acceptance of the teachers is already better because there’s an attempt to personalize the experience. And so the students are accepting the teachers more, and by the same token, I assume they’re accepting the science more.

MSDF

Have you ever thought of designing a curriculum that could be put into the science graduate programs, because these people are going to become scientists?

Mr. Alda

What we’ve actually done is introduced a curriculum into Stony Brook University where I helped the Center for Communicating Science. And there are courses for credit taught to graduate students, and in addition there’s even at least one department that requires that the students take these communication courses. So it’s beginning to be seen as an essential element of the science education. And it’s a small beginning. But my feeling has always been isn’t communication essential to science itself, don’t we need to communicate science in order for it to take place or for the benefits of science to come to the surface? And not only that, that’s practical, but for the beauty of science to be enjoyed by the whole world, you definitely need communication. And that will help more science get done, and better science get done. More people entering science, if they understand how beautiful and engrossing it is – exciting. So it seems to me that since communication is such an important part of science, shouldn’t it be taught as part of a science education so that when you graduate as a capable scientist, you’re also a capable communicator?

MSDF

Maybe you don’t even have an idea of this answer, but what got you into this passion for science?

Mr. Alda

I’ve always been curious and that made me want to know more. I started reading Scientific American in my early 20s and since then I’ve read almost every article in almost every issue. And I love it, I just love it! I mean, I put the magazine down and I read other science magazines – I read Science & Nature and Science News, which I think does a very good job. Just the other day, I just slammed it down on the table and I said to my wife, “Arlene, you won’t believe this, listen to this.” You hear these wonderful stories of things you never imagined.

MSDF

No, I agree. I mean, some people get turned off by it, some people get turned on by it.

Mr. Alda

Well, it’s hard to believe anybody would get turned off by it unless they’re not hearing it the right way.

MSDF

I think that a lot of people are turned off early because they weren’t encouraged or they were led to believe they couldn’t understand it.

Mr. Alda

Yeah, it’s true.

MSDF

I appreciate it. Thanks.

Mr. Alda

Well, thank you very much.

[transition music]

Thank you for listening to Episode Twenty-Five of Multiple Sclerosis Discovery, our final episode for 2014. We’ll be taking a two-week hiatus for the holidays, but we’ll be back with new weekly episodes starting on January fifth.

This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is vice president of scientific operations.

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

 [outro music]

[intro music]

Hello, and welcome to Episode Twenty-four of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.

This week’s podcast features an interview with Professor Aksel Siva about asymptomatic MS. But to begin, here’s a brief summary of some of the latest developments on the MS Discovery Forum at msdiscovery.org.

We just uploaded a new data visualization to our website. This one breaks down the design of MRI-related clinical trials in MS. It combines 88 trials conducted between 1998 and 2013 in a colorful, interactive dot plot. Each dot represents a point in time for a particular measurement, such as brain volume. You can sort trials by phase, and you can look at trials in aggregate or one at a time. To view this new visualization, go to the Data Viz section under the “Research Resources” tab and click on the top link.

Magnetic resonance imaging is a source of anxiety for many people with MS. Just getting into the machine is nerve-wracking, and waiting for the results is even scarier, says a recent study from PLOS One. The researchers conducting the study suggested that educating patients about MRIs might alleviate some of the dread. Even though MSer’s typically know a great deal about MRIs, understanding how to interpret their own results may help increase the bond of trust with their physicians, the researchers said. To read more about the study, visit our “News and Future Directions” section, and under “News Briefs” click on the article, “MRI Education May Benefit MSers.”

Have a burning question? A bone to pick? Something you want to get off your chest? Start a discussion! We invite you to participate in our discussion forums by making your own threads and commenting on others. Just click on the “Discussions” option under the “Forums” tab on our website to get started.

[transition music]

Now to the interview. Last week, we spoke with Professor Aksel Siva about radiologically isolated syndrome. This week he’ll be speaking to us about asymptomatic MS and approaches to medicine in Turkey.

Interviewer – Dan Keller

Professor Siva, first of all, why is it MS if it’s asymptomatic?

Interviewee – Aksel Siva

Well, that’s a very good question and very difficult. But now with the tools that we have in medicine, we probably diagnose people without developing the disease. And, again, if we look to some other neurological diseases, today we are now discussing whether we can really diagnose Alzheimer prior that the individual develop the disease with imaging, with biomarkers, and so on. So to see the same thing in MS, I think it’s not really something very different. The thing is that not all these people will develop the disease, so the way we have been trained as clinicians, to us it’s important to see clinical signs and symptoms. 

But now we have to start seeing that not everybody will develop the disease even if they do have it biologically, morphologically, or whatever you name it, however you name it. And then when they develop, we know well that all people are not going to have the same course. So these individual differences based on genetic background, maybe environmental influence, or whatever, should put a light in the way we see individuals – not a disease, but the individual with the disease rather let’s to say than the disease affecting the individuals. So I think this concept of subclinical disease, which is not only for MS, should influence our practice or our approach to our patients, and also in understanding the diseases and how to manage them. 

MSDF

Can you tell me a little bit about some of the studies that show heightened susceptibility and that possibly invoke the idea of genetics or environment?

Professor Siva

I don’t think that I am in a state of responding to this question, because this is not really my area of interest. But from the genetic studies, we know there are some people who have the susceptibility genes, some who have the protective genes, and also some genes that may probably affect the course and prognosis of the patients. But, again, to my knowledge, what we have today, the information we have, is not really unique for everybody. It’s also very heterogeneous. So we need more time, and I think that this time it’s not too far, and especially the Genetic Consortium in the US, their findings are going to bring a lot of new information in the very near future.

MSDF

What about studies on twins or just siblings. Although it doesn’t really nail down whether it’s genetic or environmental, it does speak to heightened risk. What did those show? Who looked at them and what did they find?

Professor Siva

Well, again, I’m not aware of really very new studies on twins; identical and non-identical twins, the risk is very different, it’s maybe 2 to 3% up to 5%, depending like if it’s Canada or France it changes. But when it is identical, it’s 25 to 30. To my knowledge, the Canada cohort went up to 37%, although this number, I guess, was not published, but we know this. So it’s about only one-third even in the highest identical twin studies. So the question is what happens to the two-thirds? Maybe some of them do have incidental lesions, but they don’t have the disease. What is the present state in this genetics or others, I’m not aware of.

MSDF

Even siblings who show oligoclonal bands don’t necessarily have or get the disease, is that correct?

Professor Siva

No, that’s correct. According to the Swedish study, these people did not have the disease. Maybe more important, there was a subsequent paper reported in the same cohort, they have looked in the CSF of these asymptomatic, or let’s say of these siblings with positive oligoclonal bands, and what they called immunopathic trait. They looked in some other issues, but let’s put it these people with positive oligoclonal bands and the immunopathic trait, and they have looked in some neuronal degeneration markers. And the sibling who had the disease had high levels, which shows that there was a CNS damage, and asymptomatic case it was normal. So that is very clear that, yes, if you get the disease you might have some, let’s say, the biological evidence of it together with CNS damage, whereas if you don’t get… you may have the same trait but not the disease, because you will not have CNS damage. And there might be some underlying mechanisms – immunogenetic, whatever – which controls the disease spread and clinical expression. So I think this is a major issue. 

And in the Steffano study when he had studied, again, the relatives of people with MS who had lesions – these 4% or 10% of asymptomatic cases – he also looked in the normal-appearing white matter. And in the diseased individuals it was abnormal; whereas in the people who had just those, let’s say, T2 changes, the normal-appearing white matter was completely normal, which again shows us that the CNS damage is very, very limited in people who don’t get the disease. And from the early autopsy studies, again the people in whom the autopsy had shown brain lesions, they were mostly periventricular and probably in silent areas, and there was not widespread damage as we see in people who get the clinical disease. 

MSDF

It seems Turkey is a very good setting for looking at a lot of this, because people get a lot of MRIs.

Professor Siva

That’s correct, that’s very correct, and that’s why we have so many cases. Today with contribution of another medical school from Ankara, Hacettepe Medical School, together now we have more than 86 RIS cases that we continue to follow up, some of who have converted now. 

MSDF

And RIS is radiological isolated syndrome. Do people pay for their MRIs, or why are they so apt to come in and get so many?

Professor Siva

Not really, it’s reimbursed, mostly it’s reimbursed, or if they have their private insurance because, let’s say, physician is suspecting something. And I should also confess that in some hospitals – mainly state hospitals – there is an overload of patients. Let’s say neurologists in those institutions may not find time to listen and examine the patient as they should do. So in order not to miss something, even a patient who comes with a headache may get an MRI.

MSDF

Is there a difference in Turkey of how you approach MS patients, or treat them, or follow them from in other countries that you’ve noticed?

Professor Siva

Not really. It’s, I would say, very much the same. I have started our MS clinic in 1987 here, and today we have more than 7,000 registered patients, which is really quite a very large population. This doesn’t mean that we follow all the 7,000 and more patients because many of them had been referred for second opinions, but I would say we continue to see at least half of these people. And the way the practice is here is not any different than most major European and US centers. I had spent some time at Mayo many years ago and I had some of my other colleagues now who had spent some time. So it’s more or less the same. We have all the same drugs, most of them are reimbursed. So we have many alternatives for our MS patients, although there are some restrictions for reimbursement. We need to at least try the so-called injectables in order to go to orals, or, let’s say, the monoclonal antibody therapies, but almost all are available. And according to some rules, they are also reimbursed. 

MSDF

Are there good patient support services, psychosocial and other?

Professor Siva

Not maybe so strong. That we may differ a bit from Europe and US. We do have Turkish MS Society where such services are tried to be provided, but that is not enough. We do have some MS Society chapters in some cities but not everywhere. But mostly the problem, I would say, is economical. All these services mostly are based on voluntary basis.

MSDF

Do you think that patients react the same to their disease?

Professor Siva

We do have some studies – psychologically, physically – and it’s at very similar to western theories. So actually Turks are Caucasians mostly, and therefore it’s what if we are going to call the western-type MS, that’s what we see here too.

MSDF

Are there cultural differences in various parts of Turkey how people view their disease, or is it all about the same? I mean, Istanbul is really Europe, as you move farther east you get into more Asian and Middle Eastern.

Professor Siva

I may say not really, because we get referrals from all around Turkey, and the behavior is not really much different. I should say either whether the patient is from Istanbul or from the east part of the country or the Mediterranean, it’s more or less the same.

MSDF 

Anything important to add that we’ve missed or interesting topic points?

Professor Siva

We have a large number of MS people in Turkey, probably prevalence rate is around 50 per 100,000 or more. There have been a number of prevalence studies, and this is about what we can really derive from all the studies – 50 or more even. But I have the impression that we are getting more and more MS in Turkey today, and more familial cases, which was not the case maybe 15 to 20 years ago.

MSDF

Very good. Thanks a lot.

Professor Siva

Thank you.

[transition music]

Thank you for listening to Episode Twenty-four of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is vice president of scientific operations. 

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

 [outro music]

[intro music]

Hello, and welcome to Episode Twenty-three of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.

This week’s podcast features an interview with Professor Aksel Siva about radiologically isolated syndrome. But to begin, here is a brief summary of some of the latest developments on the MS Discovery Forum at msdiscovery.org.

The role of diet in MS is a longstanding question, for which there many opinions, but few definitive answers. Researchers and clinicians know little about how diet may contribute to the risk of developing MS, and how it may help or hurt the progress of the disease once it starts. Nevertheless, patients are pushing for answers, hoping that there is more they can do to help slow their disease. We recently published a story looking into all the facts and myths of diet. We also covered what makes diet so difficult to study in a clinical setting, and where the field is going from here.

2015 is just around the corner, and deadlines are looming for submitting meeting abstracts and funding applications. Abstract submission deadlines for the Keystone Symposia are coming up in December, and ECTRIMS and the National MS Society have deadlines for funding opportunities early in January. For more details on the deadlines and how to submit your materials, go to the professional resources tab on our website and click on either “meetings and events” or “funding opportunities.”

We have also posted several exciting new job opportunities on our website. Go to the “jobs” section under professional resources to view them. And, if you’re looking for a neurologist, a laboratory technician, a post-doc, or any other position—let us know. We’ll help spread the word on our jobs section and in our weekly newsletter, and it won’t cost you a dime to reach a very choice group of MS professionals. Simply go to the “jobs” section and click on the “submit new item” button under the “Job Listings” header.

[transition music]

Now to the interview. Professor Aksel Siva is a professor of neurology at Istanbul University in Turkey. His work spans areas from clinical neuroimmunology to neuro-epidemiology to research in headaches. 

Interviewer – Dan Keller

When we met he discussed radiologically isolated syndrome or RIS and he starts by describing what it is.

Interviewee – Aksel Siva

It is by definition an individual who gets an MRI for another reason such as migraine headache or whatever. Then, it turns out that they have MS looking like lesions in their brains. You cannot explain those lesions with any other pathology. They are not related to the patient's cause of referral for an MRI. Their neurological examination is normal, and these people never have experienced any neurological symptom, which might be consistent with past history of MS whatsoever.

It is an MRI diagnosis actually. It is not a clinical diagnosis. The question is whether these people do really have subclinical MS or asymptomatic MS and are they going to develop the disease. So the question is what to do when you see these patients. And this has been recently described as radiologically isolated syndrome by Okuda et al. At that time, there were acute CSF and now Darin is in Texas and at that time his mentor Daniel Pelletier is at Yale. So they have introduced this term. There have been, I would say, three pivotal papers by the French group, Christine Lebrun and her colleagues, and from our center together with Mayo Clinic in Rochester. Then this group came together and we have formed the Radiologically Isolated Syndrome Consortium, which has been later on joined by some other centers from Europe and the U.S. 

MDSF

So if you don’t know whether these people will go on to MS or where they stand, what do you do about it? How do you follow them and how many of these people do go on to MS?

Professor Siva

The Radiologically Isolated Syndrome Consortium, we have conducted a study, which was published earlier this year in PLoS ONE and we have collected 451 cases with this syndrome. When they were followed, about 34% developed a neurological event consistent with either CIS or primary progressive MS. This means that about one-third of these people, who receive a diagnosis of radiologically isolated syndrome, in five years’ time, will develop clinical MS. And 10% of this group will develop primary progressive MS, which is very similar to what we see in two clinical cohorts. When statistically you follow these up to ten years and this is statistical, it turns out that around 55% will develop the disease. So at ten years’ time, still half of these people will not develop clinical MS. What does this mean? It is not clear, but on the other side, it seems that some people, who do have radiologically lesions consistent with multiple sclerosis and may continue to get new ones, still will not the clinical disease. We have known this from some autopsy studies started to be published in the 1960s, 70s, 80s, that there were cases, autopsy cases, where people turned out to have changes in their brains consistent with multiple sclerosis, but they never had the disease in their lifetime. We have to consider this subpopulation in both understanding the disease and when we should consider to start treatment, or whether we should really treat all people with MS or not.

MDSF

There has been a feeling that you don't treat the image, but you treat the disease, but a lot of these people do go on to get the disease. Is it time for a randomized trial to see if you treat these people, some of them who would statistically go on, will not go on to get the disease?

Professor Siva

It is time to start a treatment trial in RIS and our EOS colleagues, mainly Darin Okuda and Daniel Pelletier and Orhun Kantarci will be starting such a study in the U.S. later this year. There is also another probable trial that might start in Europe by Christine Lebrun. Yes we have come to this era, and probably within let's say a few years, we will have more evidence regarding who should be treated or who should not be when they present with RIS.

MDSF

In the study that you looked at people for five years, what did you see were some of the risk factors for going on to MS?

Professor Siva

There were some clear-cut risk factors and this was, as already shown by Darin and their group in EOS [?] a couple of years ago, having a spinal cord lesion at the time of the RIS diagnosis is a predictive factor to develop MS. Other factors are male gender and younger age; because when we have looked in this RIS cohort of the 450 or so cases, the mean age of diagnosis was 37, which is older than the general mean age that we diagnose MS. So this should be also taught whether this is because we have just by coincidence we get these incidental lesions in some people who will never develop the disease. 

MDSF

Now this study started a while ago to be able to be published recently. In that amount of time people have been looking at a lot of biomarkers. Did you consider biomarkers at that time? Can you find something that is predictive of going on to MS?

Professor Siva

Not yet. Actually this study was a retrospective study, but in part it was prospective because in our center we have been interested in this for more than ten years now, almost 15 years. I should say that in Turkey we have a lot of MRIs and the cost is very low. It is very practical for, let's say general neurologists to refer patients for headaches, for not otherwise you would refer for a MRI, to refer them to MRIs, and then suddenly you started to see this MS looking-like lesions. As we have in MS center, we had a lot of referrals and then we started to follow these people. It’s been more or less the same in the other centers. It is yes, a retrospective data collection, but most of this cohort has been prospectively followed in those centers from the time of their admittance. And your question was whether there was a biomarker other than imaging, not really. Not yet, let's put it that way.

MDSF

So is it advisable to follow them with imaging and if so, how often?

Professor Siva

It is what we are doing now. There have been some suggested algorithms, but what we do in our center, we ask those patients to have a followup MRI in six months. Then within another six months, unless they develop something clinical, and then if they continue to have changes or not in their MRIs, that depends on how frequently we start to follow them up by MRI. Our tendency is twice for the first six months and then yearly for the next two years and then three years or two years later, unless they develop a clinical event consistent with MS or whatever.

MDSF

Necessarily these interval MRIs are really snapshots, even in MS lesions come and go. I suppose it would be possible to miss a lesion that was there and that isn't there at the time of the MRI.

Professor Siva

Definitely. But it has been shown, again in our study, that about two-thirds of these people continue to have new MRI lesions, but only one-third of the whole population develop a CIS or other event consistent with MS. Having new lesions doesn't really mean that the risk is much higher. Developing new MRI lesions is not always equal to develop the disease or having a much higher risk. It has been shown by the Queen Square Group many years ago when they have followed people who were admitted with CIS for up to 20 years. Ten to 15 % of these populations who presented with CIS, mostly optic neuritis continued to have new lesions, but they never developed a second clinical attack. It is more or less, I believe, for RIS some of those people will continue to have maybe one or two lesions when you do a followup MRI, but that doesn't mean that they necessarily will develop the disease. Even having positive oligoclonal bands is not a much higher risk by itself.

MDSF

It would be quite a burden to treat 100% of the RIS population to be able to avert a progression to MS in about a third or over ten years about 55%. I guess, what you really need to do is be able to figure out who will progress. I guess a subpart of that question is, how do you know, or do you know, who will go on to primary progressive MS?

Professor Siva

Well we cannot say this when they don't have any clinical symptoms and signs, because in our center we had three such patients who developed primary progressive MS after a period of four to eight years, when we have followed them radiologically. Probably another question is, whether all primary progressive MSs are really primary progressive, or are let's say secondary progressive MS, the diagnosis was done when they have gone through all of the let's say CIS, relapsing-remitting MS subclinically, and when they have entered in the secondary progressive phase, then, the disease became clinically surfaced and because of this we thought that this was people who were primary progressive. Because when you look at these people and we had those…well the whole group, the RIS we have more such cases, which is now prepared for publication. These people continue to have new lesions and they are not really any different than the relapsing-remitting cases. This is another issue that we should consider.

MDSF

So in essence asymptomatic MS might really be MS and what looks like primary progressive is really secondary progressive.

Professor Silva

Could be. That is a possibility. If I am not wrong, it was the late Charles Poser who had suggested that a number of MS patients the disease goes subclinically for a certain period of time, but they continue to have axonal degeneration and after a certain threshold they become only clinically symptomatic. It might be an analogy between this view and what we have observed.

MDSF

Is there anything important to add on the subject of RIS?

Professor Silva

Our approach is on an individual basis. Yes, we do have some evidence, we do have some findings, but that doesn't mean that when you see an individual with RIS they will do how it is expected according to the present evidence. When I am with my patients, or I shouldn't call them patients, but the individuals with RIS, my approach is on an individual basis. If they continue to have new MRI lesions and it is really high T2 load on the MRI, we ask for a CNS study, if they have positive oligoclonal bands, they have but normal visual evoked potentials; they have family members and so on. The way I approach those individuals is a little bit different than someone who has a few lesions, just enough to make a diagnosis of RIS, but don't have really other risk factors, no spinal cord and so on. When it comes to the patients we should make our decisions on an individual basis. I do not treat people RIS, but there might be some exceptions.

MDSF

Very good, I appreciate it.

[transition music]

Thank you for listening to Episode Twenty-three of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is Vice President of Scientific Operations. 

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

 [outro music]

[intro music]

Hello, and welcome to Episode Twenty-two of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.

This week’s podcast features an interview with Dr. Paul Matthews about the Optimize project in the United Kingdom. But to begin, here’s a brief summary of some of the latest developments on the MS Discovery Forum at msdiscovery.org.

Some good news came from the pharmaceutical company Genzyme. On November 14th at 9 pm Eastern time, the FDA approved the drug alemtuzumab – trade name Lemtrada – for relapsing forms of MS. The FDA previously rejected the drug in 2013 due to concerns about study design and side effects. There is still some concern over safety, though, so the company is releasing it to only a limited number of patients. The prescription will also come with a host of other drugs to protect against harmful side effects. Researchers aren’t quite sure how the drug works, but it appears to target monocytes, T cells, and B cells.

Researchers announced a new mouse model for fatigue at the 2014 Society for Neuroscience meeting in Washington, D.C. The model works by enhancing expression of the pro-inflammatory cytokine, interleukin-1-beta. The model caused mice to reduce physical activity, without showing other signs of illness such as fever or anhedonia. Middle-aged and aged female mice were most affected by the treatment, whereas young mice showed no difference in signs of fatigue. The model gives credence to the idea that fatigue is not produced from dysfunction in the arousal system, but rather is a result of inflammation. The researchers said that they hoped the model will help illuminate the neurobiology of fatigue, the most common and debilitating symptom of MS.

If you would like to keep up with all things MSDF, please consider subscribing to our weekly newsletter. We keep our newsletter up-to-date with all of our news stories, blogs, and items from our professional and research resource sections. We’re also on Twitter; follow us at msdforum. And on Facebook, you can like us at facebook.com/ms discovery forum.

[transition music]

Now to the interview. Professor Paul Matthews is at Imperial College London in brain sciences. Last week he talked with MSDF about imaging in MS. This week we’re discussing his involvement in a UK-based project intended to optimize and personalize MS treatment.

Interviewer – Dan Keller

Welcome, Professor Matthews. You’re participating in the Optimize project in the UK. Can you tell me about that?

Interviewee – Paul Matthews

Well, thanks, Dan. Optimize has been an exciting journey and we’re still at the early stages, but let me tell you a little bit about it. Over three years ago, a number of us got together to discuss what the barriers to development of stratified or personalized medicine for multiple sclerosis was. We all recognized what the potential could be if we could really figure out how to target medicines to responders, we would have a way of most appropriately staging the introduction of different medicines across patient populations, not exposing people who didn’t need them to drugs of higher risk and insuring that those who did need them got them early. This is a particular problem in the United Kingdom where there is a much more formal process for progressing from first-line DMTs to more powerful agents. And, in fact, there’s also – dare I say it – I mean, a frank therapeutic nihilism and a surprisingly small number of MS patients receive treatment because of the perceived lack of benefit to many of these first-line therapies.

Now how to change this. I think what we realized is that we need to have much more granular data on the characteristics of patients being treated and how they fared after their treatment over the long-term. The data provided within the usual clinical context is not only limited, but it ends up being rather patchy over time. In order to enable that, we needed tools that would both collect data and incentivize collection of complete data of high quality. Now a note about this. We all know how to do this within the context of clinical trials, but it’s hugely expensive; it’s expensive because there are multiple people always involved to crosscheck that the data is completely acquired in each paper, and secondarily, there are audit procedures in place in retrospect to insure that this is being done. This really isn’t feasible in routine clinical practice.

A colleague of mine, Rory Collins, who has specialized in setting up very large-scale clinical trials in areas like China and India, has shown how very simple electronic tools can help both insure that data is acquired completely and that there is an electronic audit trail to follow-up on data that isn’t. What they showed is that by creating simple electronic questionnaires that wouldn’t let the questionnaire be closed unless data of an appropriate type was entered in the field, and then automatically interrogating the data for quality from center to center and following up where there were potential lapses, one could begin to incentivize acquisition of the right data and actually make it flow faster.

So how could we make this happen within the MS space in the UK? Well, what we realized is that the toolkits were all there. The EU IMI program already has funded my colleague, Yike Guo, who’s head of the Imperial College Data Science Institute, to create a tool built around a platform called eTRIKS. This is a data management environment that allows links to apps or iPads or any other peripheral electronic tool for very powerful distributed data capture. We then, in gathering together a number of stakeholder meetings which involved people with MS, the MS societies, a number of industry representatives, and what I’m really pleased to say is leads from fully 18 of the major MS centers across the United Kingdom pretty much ringing the country, together created the vision of building such an electronic tool, distributing the types of input devices across the different centers, and beginning to create a database that could be held centrally or in a distributed fashion using all the new tricks of modern IT.

The first thing is acquiring the data, the second is doing useful with it. The second thing that’s rather neat about the eTRIKS platform is that we have shown how it can be built to allow different levels of access, so that there can be access by high-level users who get to see the whole dataset, but also by specialized users who might want to see only a part of it – like a doctor interrogating it for his or her patient – or, importantly, a person with MS interrogating it to see how the data that they have entered stands relative to that that’s entered across the country by all patients; it allows people with MS to begin to gauge how they’re doing relative to others with their disease.

Now, I think the latter point is worth building on, because I think all of us have been hugely impressed by the power of sites like Patients Like Me to engage people with the disease in the dialog about their disease and make them full participants in capturing data information. With this kind of distributed data platform where doctors and people with MS can enter data whenever and wherever they are to a central database which can organize it and allow it then to be interrogated as needed, means that we can begin to think about asking patients to enter data on the fly from home. Why is this important? Well, this actually completely transforms the way in which we understand the disease, it really gives us a much deeper sense of the patient experience. Rather than sampling a patient once every month or once every six months, we can actually capture how they’re doing through a day. And if we add to this some extra sensor technologies – say, for example, about movement – we can literally do this from moment to moment.

So the vision thus is that if we can use these modern IT tools to capture data from distributed sources – from doctors using iPads, from patients using apps, from sensors that people with MS wear – we can capture data in a central resource that can be distributed to those for the purposes that they need it in near real-time, and in turn provide a common environment for its analysis. I think it’s exciting. Now we’re at the early stages, the basic tools have been designed, we’re starting to build the sensor technology. And our genuine hope is with the completion of the first set of agreements with one of the companies who’s been the first to really take a plunge with us, we’re going to be able to create a beta form of the tool in 6-9 months.

Now before closing, I do want to add one thing. This is an exciting vision but the notion of building a database is hardly a new one and many people have had it. There is something that’s special about this vision and it’s the thing that I’m most proud of that’s come together from all of these stakeholders. It’s the vision of creating a database that will be an open database; open to all researchers once it’s built, not held privately by those who built it. And I think this is what could become a game-changer. Moreover, we see that the tools that we’re building in order to create this – the IT tools, the distributed apps, and so on – are tools that the community should own and should be able to improve on. So our intention is fully, as this program develops, to release a software for open-access use as well as the data. Our hope is that even if this doesn’t provide the solution of the future, it will begin to incentivize this kind of practice where we all share this important data to work together to find solutions to this disease.

MSDF

Besides collecting MS-specific data, will it also look at general health and comorbidities to see how that affects outcomes?

Dr. Matthews

No. That’s a really good question. Like so many doctors now, we’re very much focused on the progressive forms of the disease. Our belief is that comorbidities make major contributions to this, and that by influencing these comorbidities we may have the biggest short-term impact on our patients’ lives. So one of the advantages of a big data capture tool is that we can capture data on all of the other disorders that afflict people with MS, as well, and begin with, again, greater granularity because of contributions from people with as well as their doctors to look at this in ways that wonderful databases like NARCOMS haven’t been able to do. This is an important task for the future and one that we really want to grasp. We’re hoping with further funding to be able to link this to bioresources, as well, and the ability to access a patient’s fluid samples for Omics analyses certainly can add greatly to this.

MSDF

Very good, I appreciate it.

Dr. Matthews

You’re welcome, Dan, it’s been good speaking to you.

[transition music]

Thank you for listening to Episode Twenty-two of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is vice president of scientific operations.

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

 [outro music]

[intro music]

Host – Dan Keller

Hello, and welcome to Episode Twenty-one of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.

This week’s podcast features an interview with Dr. Paul Matthews about imaging in multiple sclerosis. But to begin, here’s a brief summary of some of the latest developments on the MS Discovery Forum at msdiscovery.org.

We recently reported on a draft of a review released by the Agency for Healthcare and Research Quality about discontinuing disease-modifying therapies in patients with MS. Though the report’s main conclusion was that little evidence is available to assess the risks and benefits of discontinuing therapies, several MS groups came together to criticize the report during the open comment period. Groups like the National MS Society and Medical Partners 4 MS raised concerns that the review was not conducted properly and that insurance providers may use it as justification to reduce coverage of DMTs for MS. The AHRQ told Multiple Sclerosis Discovery Forum that they would consider the comments carefully and make any necessary revisions.

MSDF’s parent organization, the Accelerated Cure Project, is launching a new research resource called iConquer MS. Hollie Schmidt, Vice President of Scientific Operations at the Accelerated Cure Project, recently wrote a blog post explaining that the new initiative aims to take data and biosamples from 20,000 people with MS and make them open-access to researchers. We want your input about what you may want to do with such a resource. If you’re interested, go to the blogs section of MS Discovery Forum under the “News and Future Directions” tab and click on the blog post titled, “Invitation to Share Your Thoughts on a New MS Research Resource.”

Our list of meetings and events is ever-growing. We’ve posted multiple meetings of all shapes and sizes sprinkled throughout 2015 and even into 2016. And if you know of a meeting that’s not yet listed, please do submit what information you have. We’ll take care of the rest. Just go to “Meetings and Events” under the “Professional Resources” tab on our website and click on the “submit new item” button to tell us about your event. We’re even willing to list local departmental seminars and journal clubs.

[transition music]

Now to the interview. Professor Paul Matthews is at Imperial College London in brain sciences. He met with MSDF to talk shop about imaging in MS.

Interviewer – Dan Keller

Welcome, Professor Matthews. What do you see now as new modalities or new ways of doing imaging, and what’s coming along?

Interviewee - Paul Matthews

Thanks, Dan. Imaging continues to reinvent itself in areas particularly like MS. Magnetic resonance is becoming more and more powerful with use of particularly multiband techniques, allowing multiple coils to be used to accelerate the imaging process, and because of that being able to collect much more data to enhance particularly diffusion images. So, for example, within the Human Connectome Project, development of new multiband techniques has accelerated imaging to the point where very high resolution diffusion tensor images can be acquired in spaces of 15-20 minutes. The implications of this for MS are that we can begin to develop powerful approaches to expression of the diffusion tensor information in terms of diffusion parallel to the fibers, perpendicular to the fibers, and free diffusion that is anisotropic. This means that potentially we’re going to be able to separate out free-water contributions from those contributions arising from myelin and axonal loss, providing a very powerful complement to magnetization transfer images.

A second area of major development in magnetic resonance is the increased use of ultra-high field systems at 7T, and potentially higher, for applications in MS. The first advantage this has brought is for increased spatial resolution that can be used to begin to image cortical lesions with a really impressively enhanced sensitivity. The second area has been new kinds of contrast. The high magnetic fields allow new susceptibility-weighted contrast to be generated which provides a powerful way of visualizing vessels. It’s very clearly defining the vessels at the center of most of the inflammatory lesions, helping a little bit with differential diagnosis, but even more importantly helping us understand what the microvascular architecture is in and around lesions.

A second potential advantage of the ultra-high field is simply increasing the sensitivity of MR for applications in magnetic resonance spectroscopy. We’ve known for a long time that signals from myo-inositol can help us understand glial components of inflammatory lesions, but there’s increasing interest in applying this kind of tool to measurements of glutathione, to provide indices related to reactive oxygen species generation, and potentially also to measuring excitotoxic neurotransmitters such as glutamate.

In a completely different space, positron emission tomography (PET) has begun to play a renewed kind of role in MS. I’ve always been a little bit disappointed that more wasn’t done with it over the last decade or so since pioneering studies that demonstrated that assessments of energy metabolism based on simply the fluorodeoxyglucose signal not only discriminated people with MS from healthy volunteers, but, more importantly, began to show discrimination between different stages of the disease and a relationship to cognitive impairment, with potentially reversible components with treatment. Now, that still is an area of potential work.

But more recently focus has shifted particularly to use of ligands that bind to the 18 kilodalton translocator protein which provides a marker of microglial inflammation in the brain. While it’s not entirely specific and with the caveat that we have little understanding of the relationship between the TSPO expression and the microglial phenotype, it clearly is highlighting some very interesting things. First, we found that the TSPO binding by ligands is increased multifocally in brains of people with MS; it’s increased multifocally in the white matter and in the grey matter. Moreover, increases in binding in both regions are related to degrees of disability; patients with higher disability show increased binding particularly in the cortex.

There’s emerging evidence, driven first by elegant preclinical studies done by the Finnish group and some human studies yet to be fully reported, that there are also strong treatment effects with powerful amino modulators. So because this provided us a window that is clearly giving us information distinct from that provided by T2 hyperintense lesions on MRI or by gadolinium enhancement on MRI, it promises a powerful adjunct.

And, finally, just to kind of round that idea out, it’s clear that it will be the combination of MR and PET that’s powerful rather than PET replacing MR in some way in our diagnostic or monitoring armamentarium for treatment. One manufacturer has already started supplying commercially integrated MRI-PET systems. Another manufacturer is expected to do so very soon, and potentially a third. This may become a platform for brain imaging that is very powerful for disorders like MS that have multifocal manifestations where the registration – the precise registration – between the MRI and the PET becomes important. Moreover, the potential to use dynamic MRI acquisitions where we’re just imaging very, very rapidly throughout the entire PET scanning period to follow the position of the head within the PET scanner may allow a new kind of precision of special resolution in the PET scan that allows MS studies where we rely on this very much to be done with far greater precision than it’s been possible in the past. So with these developments in MR, with the new radioligands in PET, and with this new technology for integrated MRI-PET, I think the brain imaging is off in incredibly new spaces.

Now I can’t close the discussion of imaging without at least making a mention of the revolution in applications of optical coherence tomography that have been conducted over the last five years in particular for MS. This is really exciting, too. It’s an inexpensive examination that can be performed very rapidly in any clinic that provides very high-resolution measures of optic nerve fiber layers, of multifocal edematous regions within the nerve fiber layer, all of which can provide measures to stage MS and its associated neurodegeneration, and potentially to usefully monitor it in assessing the progress of patients on treatments. It’s an exciting time for imaging.

Interviewer - MSDF

Now just to clarify, this is optical coherence tomography of the retina and its surrounding structures.

Interviewee - Dr. Matthews

Yeah, Dan, thanks for clarifying that. Absolutely. So it’s an eye examination, but it’s an adjunct because the retina is just an extension of what we study in the brain.

Interviewer - MSDF

Either using metabolic markers or following metabolism with PET or something else, or using other ligands and markers, can you discern or image where remyelination is occurring?

Interviewee - Dr. Matthews

So, of course, the world of PET is a big one because what we can observe changes with the type of radiotracer that we use. Recently, Yanming Wang, who I had the privilege of collaborating with at Case Western, published, I think, a really groundbreaking paper. Although it was a preclinical study, I think it shows the way we could be moving in this space. Using a novel radiotracer that he developed called MeDAS – MeDAS for short – this carbon positron-emitting isotope-incorporated tracer allows specific myelin proteins to be imaged, and thus provides a marker of myelin integrity in life. Yanming has shown how it can selectively image myelin, it can image both established myelin and new myelin being formed, and he demonstrated in a proof of concept study in rodents that the dynamics of demyelination and remyelination following therapeutic intervention can be followed, and moreover, that the therapeutic effect can be quantified relative to an untreated control group.

Really exciting and a potentially important adjunct to MTR or diffusion measurements in human studies. The trick of moving a tracer from preclinical studies into humans is not without some need for care, but because only microdoses of these tracers are used for the human imaging experiment, Yanming, myself, and colleagues believe we can make this transition rapidly. We’re watching closely to see what happens next.

Interviewer - MSDF

Pretty good. I appreciate it.

Interviewee - Dr. Matthews

Thanks, Dan.

[transition music]

Thank you for listening to Episode Twenty-one of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is vice president of scientific operations.

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

 [outro music]

[intro music]

Hello, and welcome to Episode Twenty of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.

This week’s podcast features an interview with Dr. Jeffery Cohen about two clinical trials. But to begin, here is a brief summary of some of the latest developments on the MS Discovery Forum at msdiscovery.org. Genome-wide association studies are raising more questions than they answer for multiple sclerosis, according to new research. As the number of risky genetic variants grew, researchers began to wonder if many of those variants would be found in the murky waters of “noncoding DNA,” which comprises about 98% of the human genome. Those fears were confirmed in a study published last month in the journal Nature. According to the report, almost 90% of the risk variants fell within the noncoding region and 60% were found in areas known as enhancers or switches. These areas manage gene activity, though researchers are far from fully understanding how they work. While genome-wide association studies have been helpful to researchers, this study highlights that they are just a first step towards a better understanding of MS and the human genome.

The International Progressive MS Alliance recently released a call for applications for their second round of grants. To go along with this announcement, Professor Alan Thompson, the head of the Alliance’s scientific steering committee, penned a post for our blog. In his post, he emphasizes the urgent need for more research into progressive MS. He notes that over one million people worldwide live with progressive MS, yet no specific treatments exist for this condition. You can read Professor Thompson’s post in the blog section of the News and Future directions tab at msdiscovery.org. To get more information about the grants from the Alliance, visit our “Funding Opportunities” section under the “Professional Resources” tab on our website.

In addition to the latest funding opportunity from the Progressive MS Alliance, we also recently posted a long list of funding opportunities from the National MS Society.

[transition music]

Now to the interview. Dr. Jeffrey Cohen is a neurologist and director of the Mellen Center for multiple sclerosis at the Cleveland Clinic. He spoke with MSDF about two clinical trials, one examining the clinical use of stem cells, the other about a generic version of glatiramer acetate, Copaxone.

Interviewer – Dan Keller

First of all, what was the aim of the clinical stem cell trial and what phase was it done in?

Interviewee – Jeffrey Cohen

So we now have 11 medications approved to treat multiple sclerosis. They are all effective in the early, relapsing remitting stage of the disease, but there is a major unmet need for treatments that repair damage and might be effective in progressive MS. Our main goal was to explore cell-based therapies to treat multiple sclerosis, specifically to test the feasibility and safety of administering so-called mesenchymal stem cells. This was a Phase I study of mesenchymal stem cells. These are stem cells that are present in many tissues of the body. We isolated them from bone marrow which is probably the version that is the best studied previously. We grew them in the laboratory to increase their numbers, and then readministered them intravenously. We were focusing primarily on safety, as I said. We had fairly intense monitoring for any complications. Thankfully, we saw none. We also looked in a very preliminary way for benefit using clinical measures, a variety of imaging approaches and immunologic measures.

MSDF

What is the hypothesis here that they are doing? Do they actually get into the brain? You are infusing them IV. There is a blood-brain barrier, these are pretty big objects.

Dr. Cohen

There are actually a large number of studies in the laboratory and in animals that suggest that these cells have a number of properties that we think would be of use in a disease like multiple sclerosis. First of all, they seem to modulate the immune response. They dampen down inflammation. But more importantly, they appear to be able to produce a wide range of soluble factors, growth factors and other substances that we think promote repair. We think of them as the delivery system for growth factors that promote repair. We don't think that they themselves develop into brain tissue but will become neuro-cells, but rather that they create a milieu that is conducive for the natural intrinsic repair processes to remyelinate or restore neurologic function. The other property that is potentially very advantageous is that they appear to be attracted to areas of tissue damage or inflammation. They appear to have the ability to migrate within tissues, and in fact to migrate from either the cerebral spinal fluid into the brain or from the blood into the nervous system. So we think we can take advantage of that by administering them intravenously.

MSDF

Did you do dose-ranging here?

Dr. Cohen: We did not. One of the things we learned from this study is that there are a lot of unknowns about cell-based therapies. What the appropriate dose is? Whether multiple doses are needed? What is the best route of administration? Whether there are nuances as to how you grow the cells in culture? What characteristics you want to augment? Dose-ranging in particular is something that has been very difficult to do in the field, particularly for some of these cells that are grown in culture; you usually have the dose that you have. That has been an issue that we have struggled with as have others in the field.

MSDF

How long did you follow these patients and what did you find?

Dr. Cohen

We followed them for two months prior to infusion. That is the time during which their cells were being cultured, and then for six months after infusion. So very reassuringly there were no serious or severe adverse events. In fact, there were very little, if any, side effects. Patients were not immunosuppressed. They had no premedication. The only side effect was that the culture media contains a chemical called DSMO. Some patients got a garlic taste in their mouth. If they don't like Italian food, they didn't like that. We also looked in a preliminary way for evidence of benefit with the caveat that this study was not really designed to look for benefit. We used this as an opportunity to explore a variety of measures that might show tissue repair. We saw enticing improvement in some measures in some patients, but for patients as a group, there was no clear-cut evidence of benefit. We have to be very careful how we interpret these results.

MSDF

Could you follow them in any way? Were they tagged or any other way that you know where they went?

Dr. Cohen

No. That is another aspect of the cell therapy field that is getting a lot of attention. At the moment it is largely a black box. After we administer the cells, knowing whether they survive and where they go and how long they live there. That is another line of research besides pursuing further clinical trials of these cells is also to develop methods to track them within the body. There are some promising approaches that we are in the process of developing.

MSDF

Now I take it these were not modified in any way, they were just cultured to multiply them?

Dr. Cohen

There were some growth factors in the culture media, but they were from the regulatory point of view, not very manipulated. That is the terminology that is used. That is another area of debate is some of the specifics of the culture approach, whether we should add other factors that might change the properties of the cells. Whether it is okay for them to be frozen, which we do largely for convenience because then we can schedule the infusion. Or whether they should be taken fresh from the culture and administered. There are arguments for both approaches.

MSDF

Many cells seem to hone right back to where they came from. Do these just go back to the bone marrow do you think, or do you think they actually went somewhere because that area needed repair?

Dr. Cohen

There have been a few studies in some other conditions where these cells have been given. One of the interesting properties is that you can administer these cells from another person and they are not rejected. They become, I wouldn't say the standard, but a very common treatment for what is called graft-versus-host disease, which is a very severe complication of allogeneic bone marrow transplant where the transplanted immune system attacks the recipient's body. That is where the immunomodulatory effects of mesenchymal stem cells were first observed. There are, unfortunately, have been a couple of instances where MSCs that were from another person of a different gender, were administered to someone with graft-versus-host disease who unfortunately, subsequently died of GVH. In those cases, these cells were found in a range of tissues including bone marrow. Probably a more important obstacle is for after intravenous administration is the lung because that is where the blood goes from the veins. These cells probably collect in the lung initially and then percolate out into the tissues.

MSDF

Do you have any concerns, any caveats about potential harms, limitations, from using this? Is it feasible on a large scale?

Dr. Cohen

We took a very conservative approach with the idea that there are so many unknowns of cell-based therapies, including precedence in multiple sclerosis where therapies had a different effect than we anticipated. We thought it was appropriate to take a very careful systematic approach starting with a small safety study and then building from there. At least within the limitations of our study, meaning that it was relatively short, and relatively small, we saw no indications of any complications. Some of the hypothetical concerns would be cancer. Stem cells share some properties that are similar to cancer cells, or ectopic tissue formation. Stem cells have the natural ability to develop into almost any kind of tissue. At least, presumably they could go to one tissue and develop into another type of cell, so bone within the heart or something like that. We really saw no indication of that. There are really no examples of that in the literature, but because of those sorts of concerns, we took a very careful approach. We feel comfortable now moving on to a bigger program. 

MSDF

You had discussed some of the problems that arose using allogeneic cells. Just to clarify, this was using autologous cells?

Dr. Cohen

Correct. These were cells from the patient themselves. There is still some debate in the field, which approach is better. Whether to take cells from the person themselves or whether to take cells from someone who does not have the disease that you are treating. That again is an issue that has not been settled. I think some of the cell tracking we were talking about earlier may help with that. Rather than answering all of these questions one trial at a time, we may be able to adjudicate some of these questions by seeing whether cells traffic more effectively.

MSDF

Let’s shift to your other trial, the GATE trial using generic Copaxone. Is that available now and what was the point of the trial?

Dr. Cohen

The purpose of this trial was potentially to have a generic version of one of the established multiple sclerosis drugs come available. The incentive would be that presumably because of the lower development costs, that the generic version would save money for payers and for patients. The trial we just completed was of a generic version of glatiramer acetate, Copaxone, one of the initial drugs approved to treat MS, a drug that we have a great deal of experience with. It has established efficacy and a known good safety profile. This study tested a generic version of that with the intent of showing that it had equivalent efficacy, in this case, as tested by MRI and had equivalent safety and tolerability.

MSDF

These were all patients with relapsing, remitting MS? You had, what, about 735?

Dr. Cohen

Correct. This was in a patient population with relapsing, remitting MS; the population for which Copaxone is approved.

MSDF

What were the interventions, the test group?

Dr. Cohen

There were three groups in this trial. One group was treated with generic glatiramer acetate. One group was treated with the brand Copaxone and then there was also a small placebo group to demonstrate what is called study assay sensitivity. The purpose of which was to show for the trial overall that the generic glatiramer acetate is equivalent to the brand-name, the reference drug as it is called, but also that within this trial with this population, that both drugs were effective.

MSDF

Where was this done, and is that ethical?

Dr. Cohen

One of the things we have encountered increasingly in developing multiple sclerosis drugs is that there are ethical and practical issues to including placebo groups. At this point it has become extremely difficult to include a placebo group in a large Phase III study that goes on for several years. In this case, this was a short trial, with the advantage of using MRI as the endpoint. It was conducted to some extent in North America, but primarily in Eastern Europe and other  countries where unfortunately, multiple sclerosis treatments are not as available. 

MSDF

What did you find?

Dr. Cohen

The study was successful. It showed equivalent efficacy as measured by gadolinium-enhanced MRI, and also showed equivalent safety and tolerability as measured by adverse events and injection site tolerability.

MSDF

What would this mean for patients if someone brought out a generic?

Dr. Cohen

The hope would be, is that if this drug is approved, that it would be less expensive. Multiple sclerosis is an expensive disease to care for and a great part of that cost is medication costs. So the hope would be that this would be less expensive. The other caveat is that complicated molecules such as Copaxone are difficult to replicate. In addition to very extensive chemical and biophysical analyses, that is why a trial was conducted, because of the feeling that it would only be with clinical data that we could…we assure ourselves that this was in fact similar to Copaxone.

MSDF

I would take it, that this would only apply to the generic you tested. I mean generics have a certain tolerance level margin compared to the approved brand, so not all generics are the same.

Dr. Cohen

That is correct. It is actually quite tricky to develop a generic of a complicated molecule, either a complex mixture such as glatiramer acetate or a so-called biological like a monoclonal antibody. Each one has to be tested one at a time.

MSDF

Anything important that we have missed, or to add?

Dr. Cohen

This trial was designed with the assistance of, and discussions with EMA, the European Regulatory Agency. It has been somewhat more difficult in the United States. The FDA is still somewhat unclear on their policies and the procedures for testing complex generics and biosimilars. The status of this trial in the United States is still somewhat uncertain.

MSDF

Very good. Thank you.

Dr. Cohen

Thank you.

[transition music]

Thank you for listening to Episode Twenty of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is vice president of scientific operations. 

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

[outro music]

[intro music]

Host – Dan Keller

Hello, and welcome to Episode Nineteen of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.

This week’s podcast features the second half of an interview with Dr. Samuel Ludwin. This time Dr. Ludwin and I discuss the implications of treating multiple sclerosis subtypes. But to begin, here is a brief summary of some of the latest developments on the MS Discovery Forum at msdiscovery.org.

This week we reported some good news: a large case-controlled study showed that there is no causal link between vaccines and multiple sclerosis. However, the study came with the caveat that there is some increased risk for developing MS in younger patients who receive vaccines. This increased risk is likely due to the vaccines triggering a pre-existing asymptomatic condition, the researchers said. The study, which was published in the journal JAMA Neurology, was most concerned with the role that vaccines for hepatitis B and human papillomavirus play in the long-term risk for developing MS.

We also reported on a new iPad app that will allow clinicians and MS patients to track their disease course. The app, called Bioscreen, is currently in beta-testing at the University of California, San Francisco. The developers, including Pierre-Antoine Gourraud who is on MSDF’s scientific advisory board, assert that Bioscreen has the potential to be a powerful tool for researchers, clinicians, and patients. At the core of the app is a dataset of around 600 patients who have been participating in a data collection survey for the past 10 years. Physicians can compare their patient’s disease course with other confirmed MS cases and use that information to influence their recommendations. The researchers also believe that patients’ ability to visualize their own disease in this way will improve adherence to medical recommendations and ultimately strengthen the bond between patient and physician.

Every week we publish at least one “Research Roundup” where we curate stories from around the web related to multiple sclerosis. Recently we published roundups about advances in spinal cord injury treatment, the recipe for selling the perfect bogus drug, and the report of a rare brain infection in a patient taking dimethyl fumarate, trade name Tecfidera. To view Research Roundups, go to the “News Briefs” section of the “News and Future Directions” tab at msdiscovery.org. Look for the blue Research Roundup logo and stay up-to-date with all the latest MS news.

[transition music]

Now to the interview with Dr. Samuel Ludwin, a neuropathologist who is currently a visiting scientist at the Montreal Neurological Institute. Last week we aired an interview with Dr. Ludwin in which he discussed remyelination therapies. This week he speaks with MSDF about MS subtypes.

Interviewer – Dan Keller

Welcome, Dr. Ludwin. Let’s talk about some of the subgroups of multiple sclerosis, as has been proposed by Professor Hans Lassmann, and you wrote an editorial some time ago about it. First of all, can you tell me what subgroups he identified and what progress there has been made since then?

Interviewee – Samuel Ludwin

This is a very groundbreaking paper, very controversial, and over the years many people who have followed this particular pattern, others who’ve not been able to reproduce it and believe that the conclusions are not valid. However, what Claudia Lucchinetti and Hans Lassmann showed in a mammoth first-time examination of very acute lesions; they had access to a particularly unique group of specimens that are from both the Mayo Clinic and other areas, where very early lesions were examined. And in looking at this, they looked at patterns of tissue breakdown and the mechanisms of tissue breakdown, and essentially came up with four different categories. The two most important ones are very important to discuss because in the one, the features were very, very consistent with the kind of immune injury that one finds in experimental allergic encephalomyelitis where we know the damage has been caused by the injection of the antigen with a subsequent immune reaction to that antigen. And the other main group was one where there appeared to be a primary damage of some sort to the oligodendrocyte and then a subsequent immune reaction.

Now this is important for a couple of reasons, and the first is that there is a big debate going on in the multiple sclerosis literature or research as to whether the disease starts from the outside peripheral activation of immune cells and then homes in on the brain because they are cross-antigens or cross-antibodies or cross-cells, or whether the process actually starts with damage to something in the brain which subsequently sets off the – and this is called the “inside-out” or “outside-in” controversy at the same time. What this might mean, according to the way they have done the study – which was a very good one – was they suggested that there might be multiple mechanisms towards the end result of damage to oligodendrocytes and myelin, and subsequently the physical appearance of multiple sclerosis lesions.

Other people have challenged this and suggested that maybe it is a question of timing, and the mechanism is the same in all patients, but we’re looking at a different kind of progression and timing. And that controversy is still being discussed, as is the inside-out, outside-in phenomenon. But when you look at some of the things that might be causing these inside-out or their type 3 pattern where the primary damage could be in the oligodendrocyte, there are many reasons that the mechanism could be due to either stroke-like causes such as a lack of oxygen or blood flow that damages the oligodendrocyte, possibly certain infections that may target the oligodendrocyte. And we know that there are many mouse models where you can target oligodendrocytes with certain viruses. And those overlap very significantly with mechanisms of tissue damage in other diseases.

So it is a very important paper because it has set people thinking about multiple mechanisms. The fallout from this is that, in fact, when you have different mechanisms of causing disease, there are potentially different ways of treating it. And if you have a primary immune-based phenomenon from the outside, antiinflammatories as are given on disease-modifying therapies are perhaps the way to go, whereas if you’ve got something that is damaging it from the inside and some other cause, we need to elucidate what that cause is and go straight for that particular cause. In addition, what we are trying to find out is whether we can predict what sort of pattern has caused the disease, either with imaging or with biomarkers, and be able to do this without biopsies and other things so that patients can be treated accordingly. It’s an advance on perhaps what we might call personalized medicine in multiple sclerosis. 

MSDF

Are there imaging or clinical correlates of these different types of processes? You’re not going to do a biopsy on most people.

Dr. Ludwin

No, there isn’t. But in fact, there are some therapeutic differences. For instance, in the type 2 pattern, which is the autoimmune pattern or the outside-in pattern, these patients respond very well to plasmapheresis where one is removing the offending gammaglobulin. And patients with the type 3, which is the main oligodendrocyte-based pattern of the disease, they don’t respond to that well. And that’s perhaps the best clinical differentiation that we know at the moment that helps us. A lot of the data is not clear. They based a lot of the data on the fact that they felt that every patient had a uniform pattern in the lesions. Other people have questioned this and found that there might be a multitude of different kind of patterns in the same patient, and therefore it supported modifications of the same inherent cause.

MSDF

Does the efficacy of plasmapheresis correlate with the presence of oligoclonal bands in the CSF, or that’s not a correlation?

Dr. Ludwin

There doesn’t seem to be a correlation, leastwise I know. Certainly plasmapheresis where we know that there is antibody, such as in neuromyelitis optica is more effective as a treatment early for diseases where we know that there is circulating antibody, but patients will have oligoclonal banding, I think, in both patterns.

MSDF

You’d alluded to damage to the oligodendrocyte in one of these forms as the primary dysfunction or lesion. Does that imply that something is being exposed, an antigen that might be reacted to, or how is that leading to damage?

Dr. Ludwin

Absolutely, that if you get damage to a tissue, various proteins are being broken down and antigenic epitopes are being exposed, which then are transported back to the peripheral lymphoid tissue for reactions to take place. I mean, there are counter-arguments to this. One can ask why, with a lot of trauma injury, a lot of stroke injury which is far more common than MS, why you don’t get a secondary immune response to that, even though we know many people with the genetic makeup makes them susceptible to MS or exist in the normal population, and almost certainly some of them have strokes. So there are questions on both sides and arguments. And we know from other experiments that you can induce circulating antigens with tissue destruction of any cause, and potentially these are circulating to be able to produce reactive antibodies in the periphery.

MSDF

I think Lassmann showed that even in healthy people you can find CNS antigens in the cervical draining lymph nodes, which raises the same question you just brought up; why do some people have a reaction and some not?

Dr. Ludwin

Absolutely, and there are now all sorts of theories coming out of the genetics that there are multiple genes, each having a small effect, but in totality may be adding up to a genetic defect that will allow some of these circulating cells to suddenly start having an effect.

MSDF

Now it seems, in terms of thinking of personalized medicine, so much of it is empiric – what works works, and you try something else if it doesn’t. Is there a possibility of any harm from these treatments to people for whom it doesn’t work? Do you have to be very concerned about also first not do harm, especially considering you can’t tell the difference among these types from the start?

Dr. Ludwin

Yeah, I think that it’s too early to apply personalized medicine to patients in this particular area in the different types. If you’re looking at personalized medicine that, you know, we treat patients as individuals, or we should, because a lot of the therapy is based on empiric choice and anecdotal experience sometimes with the clinician, and there’s no absolute algorithm that everybody uses to treat a patient. So in that sense, we already do practice it. But you’re quite right, a lot of that is anecdotal or empirical rather than mechanistic.

The do no harm is a very interesting point also, because you mustn’t forget that basically multiple sclerosis is an inflammatory disease, and very frequently we tend to look at inflammation as being something that’s bad. But the reason the body mounts an inflammatory infiltrate is usually to cure something or to clean up something that is attacking it from the outside. So in any kind of these interferences, we have to choose a very find balance between stopping an inflammatory infiltrate or reaction that may be doing a lot of good for the patient, while preventing it from its worst excesses.

And here, empiricism comes in quite well at the moment; we know which of these drugs that we give are more likely to give side effects, we know more about side effects than we do about potential for not allowing growth. We will stop a particular cytokine or block a particular protein in its action, but I think we should always be aware that the protein, if it’s a normal one and not abnormal protein, may be there for a reason and the patients will do worse if they don’t have this mess cleaned up, so to speak.

MSDF

We’re also finding today that we’re almost living in a proinflammatory environment; it has repercussions in heart disease, dental disease, MS, fat is proinflammatory. So do all these things add to the risk in MS if there’s other inflammatory processes going on?

Dr. Ludwin

Well, it’s not only the inflammatory processes that’s going on, it’s the things that are causing them. As you’re right, we are now discovering that things like salt, fast foods, the changes in the microbiota all tend to make us more proinflammatory. And certainly in experimental animals and now some human studies, it has been shown that experimental immune disease is worsened by a high salt intake which leads to increased salt in the tissues, as well as being prevented by some of these diseases. If you change the gut microbiota in many of these diseases from normal commensals into something that may be pathogenic, you will set off inflammatory autoimmune disease. It’s been shown very beautifully in ulcerative colitis and Crohn’s disease, and the same thing is now being looked at very strongly in multiple sclerosis, so certainly a proinflammatory environment.

On the other hand, it should be remembered that there’s certain kind of infections that produce a reaction that may very well be protective, and there’s some evidence that some of the parasites produce a factor and we believe it could be related to a particular type of protective T-cell that will then allow for patients to become resistant to multiple sclerosis. And there’s some very good data from South America that populations who’ve been exposed to parasites and have them are actually more resistant to multiple sclerosis, because the parasite has induced a protective antiinflammatory molecule in the cell as well. So it’s a very complex balance and we’re gradually discovering more and more about where this balance lies.

MSDF

Might the prevalence of parasites account, at least in part, for the geographic distribution of MS?

Dr. Ludwin

Well, parasites are just one part of it. There is a very strong feeling, and it comes back to also the gut microbiota – but it’s more than just gut microbiota; it’s environment microbiota – that this has a major role. And for many years, it wasn’t just parasites. People in the Third World had a much lower incidence of multiple sclerosis, and this could have been also from genetic reasons or from susceptibility. But it was not just for multiple sclerosis. All autoimmune disease was much lower in frequency in these populations, and the theory was that most of the people who grew up in developing countries were exposed to large numbers of bacteria and they developed robust immune systems, normal-functioning immune systems that could help them deal with it. And the theory is that in developed countries, the over-usage of antibiotics has aborted normal immune responses, and so in response to that autoantibodies are created and we are suffering the consequence of living too clean a life. And so I think if you look at that argument, it’s not just multiple sclerosis, it really has been mooted for the inflammatory bowel disease, juvenile diabetes, rheumatoid arthritis, and other immune diseases as well.

MSDF

Thank you, this has been very good.

Dr. Ludwin

Pleasure.

[transition music]

Thank you for listening to Episode Nineteen of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is vice president of scientific operations.

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

[outro music]

Hello, and welcome to Episode Eighteen of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.

The term “neuroscience” makes it very clear who is the star of the show—neurons. But over the past few years, glial cells have been elbowing their way in from supporting cast to stars in their own right. We recently reported a story about how oligodendrocytes need to make new myelin in order for mice to learn a new motor task effectively. The study demonstrated how glia are required in active learning, as well as highlighted the importance of targeting remyelination in new therapies for demyelinating disorders.

Finally, we recently added a new data visualization examining the differences in baseline characteristics of patients in 74 RRMS and CIS clinical trials. You can easily see how individual trials compare to the overall mean values of gender, age, Expanded Disability Status Scale score, the number of gadolinium enhancing lesions, and the volume of T2 lesions. To see the new data visualization, click on the “Data Visualizations” tab under “Research Resources,” and then click on “RRMS and CIS baseline characteristics.”

In terms of remyelination, what do we know now? Are there new thoughts about mechanisms and are there any compounds in development that would facilitate it?

Interviewee—Samuel Ludwin

It is interesting that some of the drugs are either approved for other uses or they are older drugs or derivatives of older drugs that are now resurfacing in this arena. How do some of those work?

Dr. Ludwin

It sounds like those have sort of general repair functions. I mean they are using estrogen or testing it in traumatic brain injury and things like that.

Dr. Ludwin

Now I guess there is a difference between neuroprotection and remyelination. Some of these drugs do both or do they fall into separate categories?

Dr. Ludwin

You hear much more in terms of reperfusion injury, the role of excitotoxicity, particularly glutamate. Does that also enter here or is this such a chronic process that you really don't have an accumulation of glutamate?

Dr. Ludwin

On these topics, either compounds that look promising or the process of repair itself, what have we missed, or is there anything important to add?

Dr. Ludwin

Very good, I appreciate it.

[transition music]

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

 [outro music]

[intro music]

Host – Dan Keller 

Hello, and welcome to Episode Seventeen of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.

This week’s podcast features an interview with Dr. Hans Lassmann about the usefulness of animal models for studying multiple sclerosis. But to begin, here’s a brief summary of the developments at the MS Discovery Forum at msdiscovery.org.

In the progressive stage of multiple sclerosis, some astrocytes appear to upregulate genes that intensify inflammation and neurodegeneration. Researchers think that genetic changes cause astrocytes to release a fatty molecule that beckons inflammatory monocytes from the blood into the brain. A drug, miglustat, currently used in the treatment of Gaucher’s disease, may be a good candidate to repurpose as a drug to inhibit astrocytes from initiating this destructive process.

The so-called “long life” protein, Klotho, may hold the keys to remyelination. Named after the Greek goddess responsible for “spinning the thread of life,” an abundance of Klotho leads to longer lifespans in mice. The protein has also been associated with numerous age-related conditions such as Alzheimer’s disease. Recent research noted that reduced Klotho was associated with myelin degeneration in normal, aging Rhesus monkeys. A small molecule, currently known as ‘Compound A’ can promote Klotho in the CNS of mice, enhancing remyelination in the cuprizone mouse model.

We recently released a new data visualization comparing various characteristics – such as age, gender, and EDSS scores – across 74 clinical trials. You can look at each characteristic in every trial, or compare the means of all the trials. To view, go to the “research resources” tab at msdiscovery.org and click on “data visualizations.” Then click on “RRMS and CIS – Baseline Characteristics.”

[transition music]

Now to the interview. Dr. Hans Lassmann studies the pathogenesis of inflammatory diseases at the Center for Brain Research at the Medical University of Vienna in Austria. He met with MSDF at the MS Boston meeting in September to discuss demyelinating disorders.

Interviewer – Dan Keller

In terms of what we can learn from other demyelinating diseases, ones caused by infectious agents, how can this shed light on the processes and possible treatment of MS?

Interviewee – Hans Lassmann

That depends, obviously, on the models which we are looking. I think there is a major difference between multiple sclerosis and these other experimental models, because the experimental models which really induce large areas of demyelination always are associated with infection of oligodendrocytes. But in multiple sclerosis, there is actually no indication that oligodendrocytes are infected. Now this has consequences that also the demyelination is different in these experimental models because it follows the death of single infected oligodendrocytes. That means that lesions have, more or less, some sort of moth-eaten edges where single oligodendrocytes are falling apart with small pieces of demyelination in between intact myelin, whereas in multiple sclerosis the demyelination is a sharply demarcated lesion which does not follow the oligodendrocyte territories. What we, however, can learn from the models is the question how the brain handles an infectious process in the white matter with respect to inflammation and the amplification mechanisms of tissue injury in the demyelinating process. 

MSDF

So are they similar enough that we can discern something useful from it, even though the patterns do seem to differ in some ways?

Dr. Lassmann

Yes, we can. For instance, there is a major difference between the autoimmune models which we have and the virus models. The autoimmune models are predominantly mediated, or driven, by an MHC class 2 CD4-positive T cell response, whereas the virus models are predominantly driven by a CD8 T cell response. Interestingly, in multiple sclerosis, also the CD8 T cell response dominates. So we can actually learn a lot from these models on the mechanisms of CD8-mediated inflammation in the brain, and also on what are the consequences of a CD8-mediated inflammation in the brain with respect to tissue injury. 

MSDF

What about some of the diseases that are closely associated with MS but are distinct from it, like neuromyelitis optica and, I guess, concentric sclerosis and others, how do they shed light on things, if they do?

Dr. Lassmann

I think they shed a lot of lights on that. Let’s take first neuromyelitis optica. Here we are in a very favored situation because we know it is an autoimmune disease and we know the specific target antigen, and the specific target antigen is a water channel in astrocytes. So from that we have actually learned how antibodies against these astrocytes actually induce the tissue injury, in that case, by first destroying the astrocytes themselves, and then secondarily leading to oligodendrocyte destruction and demyelination, and also some axonal loss. So that actually is a perfect model for a scenario where T cells and pathogenic antibodies play a role in disease mechanisms, and that is apparently also the case in a subset of multiple sclerosis patients, but only in a subset. 

MSDF

How does the glia enter into this, both as a target and maybe as a mediator or effector?

Dr. Lassmann

Now, obviously, the prime target in multiple sclerosis is the oligodendrocyte and the myelin sheath, but there is obviously also pathology in other glial cells. There is an astrocytic pathology, and there is also a microglia activation and pathology in these cases. Now, the astrocytic pathology itself may also contribute to the lesion propagation because when astrocytes are also destroyed in the lesion, or primarily destroyed in the lesion, it will also secondarily lead to the oligodendrocyte loss and demyelination. This is a classical example of neuromyelitis optica. 

MSDF

Is that through mechanisms of macrophage activation, or debris, or mediator release, or toxic release?

Dr. Lassmann

No. From the astrocyte pathology, it’s so that the astrocytes and the oligodendrocytes are connected with gap junctions, and the astrocytes play a major role in supporting the energy demand of oligodendrocytes. So if you kill out the astrocytes, the oligodendrocytes starve to death.

MSDF

Now that you bring up energy, can we learn anything from mitochondrial diseases and their consequences?

Dr. Lassmann

Yes, here we can learn a lot because the mitochondrial injury and damage is in the center of neurodegeneration and demyelination in multiple sclerosis. In that case, in the disease the mitochondrial injury is apparently driven and induced by oxidative injury, but that it leads in a secondary consequence also to mitochondrial gene deletion, so to deletions of mitochondrially-encoded genes. And here the mitochondrially-encoded gene deletions are also present in many mitochondrial diseases, and for that, obviously, mitochondrial diseases are perfect models to study these aspects of multiple sclerosis pathogenesis. A key issue, for instance, is the mechanisms of mitochondrial quality control. Normally, it’s so that the damaged mitochondrion is just removed from the cell in autophagosomes. But this needs very specific mechanisms of recognition. If this quality control is actually missing or disturbed, then these damaged mitochondria can expand, can clonally expand, and then you get an upward cells having more and more and more damaged mitochondria. And that’s, for instance, also a mechanism which is very prominent in mitochondrial diseases. 

MSDF

Is that a failure of phagosomes? Is there a defect at that level?

Dr. Lassmann

No, I think it’s rather a defect in the mitochondrial proteins, because the mitochondrial proteins are expressed on the surface indicating the phagocytic system, whether they are intact or damaged. And when this process is more or less disturbed, then the phagosomes don’t recognize the damaged mitochondria anymore. 

MSDF

What are you doing now? What sort of paths are you pursuing in terms of these things that we’ve been discussing? 

Dr. Lassmann

We have in principles three major projects. The first is that we try to define more precisely what is the nature of the inflammatory response in multiple sclerosis and in to what extent this is different from what is seen in the respective experimental autoimmune models. Now, the second project deals with mechanisms of demyelination, and here the key question is there is soluble demyelinating factor in multiple sclerosis, but it’s not very clear what exactly the soluble factor is; it could be demyelinating antibodies, and that can be modeled in experimental models, like autoimmune encephalitis. But many data suggests that there must be other factors which are not immunoglobulin and not antibodies which are responsible for this demyelination. And then the third project deals with the progressive stage of multiple sclerosis, and here it’s the central pathogenic pathways, oxidative injury and mitochondrial injury. And our projects now go in the direction of what is the course of this massive oxidative damage in multiple sclerosis, how does that relate to mitochondrial injury, and what is the consequences then on the tissue with respect to energy deficiency and other things. 

MSDF

In progressive disease, do you see a shift towards more mitochondrial damage and oxidative damage or stress?

Dr. Lassmann

We have oxidative damage already in the early stages of MS, but in the early stages of MS the oxidative injury seems to be mainly driven by the inflammatory component; that means by inflammation, activation of microglia and then the production of reactive oxygen-producing enzymes. In the progressive stage of MS, we get additional amplification factors for oxidative injury, and they are related to brain aging and related to accumulation of lesion burden. So what we get, on the one hand, an age-related increase of iron in the human brain, and iron can massively potentiate oxidative injury by a reaction which is the so-called Fenton reaction. The second thing is that you have accumulated tissue injury in multiple sclerosis with retrograde and anterograde degeneration, and that leads to progressive microglia activation, which then can actually be transformed more easily in cytotoxic microglia cells by additional proinflammatory stimuli. And the third mechanism is that the mitochondrial injury increases, and in particular the mitochondrial gene deletion and the clonal expansion of defective mitochondria expand in the progressive stage with disease duration. And mitochondria, when they are damaged, they can liberate electrons, and the electrons can actually, again, react with oxygen, producing a reactive oxygen species. And so this is a more or less self-amplifying process which then leads to enhancement of neurodegeneration and demyelination. 

MSDF

Is there a role for glutathione here?

Dr. Lassmann

Yes. Glutathione is one of the key molecules for the oxidative injury, and obviously this is one of the players, but it’s only one. 

MSDF

It’s a player in the injury or in limiting injury?

Dr. Lassmann

That is not entirely clear yet.

MSDF

What have we missed or you think is important to discuss or add?

Dr. Lassmann

There is certainly in the multiple sclerosis therapy also the tests to increase remyelination and possible regeneration in the lesions, including stem cell therapies or increasing remyelination by soluble factors by cytokines and growth factors. This is all very interesting, but the key point is that as long as the disease process is active, newly-formed myelin is destroyed relatively quickly. 

MSDF

It seems that there’s almost an analogy to osteoporosis where it’s a balance between formation and destruction. Is there ongoing remyelination or turnover in the healthy brain?

Dr. Lassmann

Yes, there is a myelin turnover in the healthy brain, but there is also a profound attempt for remyelination in multiple sclerosis lesions. And what you see even in the early stages in very active MS lesions, you always find signs of ongoing remyelination. But, interestingly, in these early stages, really established remyelination is generally missing, and we have performed a study on that issue showing that if you have disease activity, the remyelinated areas are actually more prone to show new demyelination compared to the normal old myelin which is in there. So that suggests that this remyelination is present and all attempts are present, but this process is relatively instable as long as the disease process is active.

MSDF

Is there a thought of being able to inhibit that further, or accelerate a destructive process in these remyelinated areas?

Dr. Lassmann

I think this is not really specific for the remyelinated areas. If we are a [?], for instance, that disease process or the progression of the tissue damage can be stopped, for instance, with measurements making some sort of mitochondrial protection, or with certain antioxidative therapeutic strategies, then it will certainly be beneficial both for the old lesions and the newly formed lesions and the remyelinated lesions. But that’s more or less something which has to be solved before we can think of really effective remyelinating strategy.

[transition music]

Thank you for listening to Episode Seventeen of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is vice president of scientific operations. 

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

[outro music] 

[intro music]