Multiple Sclerosis Discovery: The Podcast of the MS Discovery Forum

Interview with Richard Cohen

Interview with Marc Stecker, the Wheelchair Kamikaze

[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.

Multiple Sclerosis Discovery -- Episode 98 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 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.

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

[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.

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

[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.

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

[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.  

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

[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.

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

[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.  

Multiple Sclerosis Discovery -- Episode 92 with Dr. Shiv Saidha

[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.  

Multiple Sclerosis Discovery -- Episode 91 with Dr. Jorge Nogales-Gaete

[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.

Multiple Sclerosis Discovery -- Episode 90 with Dr. Daniel Hartung

[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.

Multiple Sclerosis Discovery -- Episode 89 with Dr. Charity Evans

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.

Multiple Sclerosis Discovery -- Episode 88 with Dr. John Hart

[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.

Multiple Sclerosis Discovery -- Episode 87 with Dr. Ellen Mowry

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.

Multiple Sclerosis Discovery -- Episode 86 with Dr. Pavan Bhargava

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