Multiple Sclerosis Discovery: The Podcast of the MS Discovery Forum

Multiple Sclerosis Discovery Forum
  • 4.9 (13)
  • MEDICINE

The Multiple Sclerosis Discovery Forum (MSDF) is an online resource that aims to accelerate progress toward cures for multiple sclerosis and related disorders by sparking new ideas and catalyzing unforeseen connections. The site focuses attention on what is known and not yet known about the causes of these conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we will open new routes toward significant clinical advances. The podcast will include the latest in MS research news as well as one-on-one interviews with prominent MS researchers and clinicians. While the podcast is intended mainly for other researchers and clinicians, we welcome people with MS, their caregivers, and anyone else with an interest in multiple sclerosis and related disorders.

  1. 04/25/2018

    Interview with Richard Cohen

    Multiple Sclerosis Discovery: The Podcast of the MS Discovery Forum

    34 min

  2. 01/25/2018

    Interview with Marc Stecker, the Wheelchair Kamikaze

    Multiple Sclerosis Discovery: The Podcast of the MS Discovery Forum

    33 min

  3. 09/02/2016

    Multiple Sclerosis Discovery -- Episode 98 with Dr. David Baker

    [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.

    16 min

  4. 09/02/2016

    Multiple Sclerosis Discovery -- Episode 97 with Dr. David Baker

    [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 d

    15 min

  5. 08/26/2016

    Multiple Sclerosis Discovery -- Episode 96 with Drs. Bibiana Bielekova and Mika Komori

    [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 –

    19 min

  6. 08/19/2016

    Multiple Sclerosis Discovery -- Episode 95 with Dr. Michael Levy

    [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.

    11 min

  7. 08/05/2016

    Multiple Sclerosis Discovery -- Episode 94 with Dr. Oscar Fernandez

    [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.

    10 min

  8. 08/05/2016

    Multiple Sclerosis Discovery -- Episode 93 with Dr. Lilyana Amezcua

    [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,

    12 min
See All (100)

Ratings & Reviews

4.9
out of 5
13 Ratings

About

The Multiple Sclerosis Discovery Forum (MSDF) is an online resource that aims to accelerate progress toward cures for multiple sclerosis and related disorders by sparking new ideas and catalyzing unforeseen connections. The site focuses attention on what is known and not yet known about the causes of these conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we will open new routes toward significant clinical advances. The podcast will include the latest in MS research news as well as one-on-one interviews with prominent MS researchers and clinicians. While the podcast is intended mainly for other researchers and clinicians, we welcome people with MS, their caregivers, and anyone else with an interest in multiple sclerosis and related disorders.

Information