Multiple Sclerosis Discovery -- Episode 4 with Dr. Michael Racke

[intro music]  Host – Dan Keller   Hello, and welcome to Episode Four of Multiple Sclerosis Discovery, the Podcast of the MS Discovery Forum. I’m your host, Dan Keller.  This week’s Podcast features an interview with Dr. Michael Racke about the potassium channel Kir4.1 and its potential role in MS. But to begin, here’s a brief summary of some of the topics we’ve been covering on the MS Discovery Forum at msdiscovery.org.    Researchers at the University of California San Francisco have developed a new remyelination assay that allows high through-put drug screening. The assay takes advantage of oligodendrocyte’s tendency to wrap myelin around anything axon-shaped, such as plastic fibers and microscopic glass pillars. The assay has already identified several FDA-approved drugs as candidates for remyelination therapies, including an over-the-counter antihistamine now in phase II clinical trials.   In another article, we report on a new study that sheds light on the ameliorating effect of ultraviolet rays on inflammation and disease progression in mouse models of MS. In the study, MS patients sat in a therapeutic UV chamber for five sessions a week for six weeks. Even after one session, the patients had an increase in dendritic cells and regulatory T-cells. In follow-up studies with EAE mice, the researchers uncovered a possible mechanism by which these regulatory T-cells migrate to the central nervous system.   In addition to covering the latest in MS research, the MS Discovery Forum also curates news stories from around the web in our twice-weekly Research Roundup. Last week we wrote about the findings in phase III trials of daclizumab, a legal dispute between drug companies Acorda and Actavis, and a new collection of immunology papers from the journal PLOS. We also posted some social media advice as well as the amusing hashtag #yomanuscipt. Our favorite tweet: Yomanuscript is so bad the null hypothesis rejected it. Check out Research Roundup under the news brief section in the News and Future Directions tab on our website.   [transition music]   Now to the interview. Dr. Michael Racke is the Chair of the Department of Neurology at the medical school at Ohio State University. He’s here to discuss the latest findings of the potassium channel known as Kir4.1 and its implications for MS. MS Discovery’s Executive Editor, Bob Finn, spoke with Dr. Racke.    MSDF Dr. Racke, welcome. Dr. Racke Thanks.  MSDF So what is Kir4.1? Dr. Racke   So Kir4.1 is a what’s called a potassium inward rectifying channel that’s expressed on the end-feed of astrocytes and also on oligodendrocytes. And so it’s important for trying to adjust the right concentration of potassium in and outside of a cell.  MSDF   And what is its relationship to MS? Dr. Racke   Well, there’s been a lot of interest recently. There was a paper published in the New England Journal now almost a year and a half ago, I believe, from Bernhard Hemmer’s group that showed that about 50% of MS patients have antibodies directed against this potassium channel, Kir4.1. MSDF   And is that a lot more than people without MS? Dr. Racke   Right. So when they looked at healthy individuals or looked at patients with not just neuroimmunologic diseases but also other non-inflammatory diseases, the number of antibodies directed against it was very low, on the order of magnitude of like 3%.  MSDF   So what does this mean for our research in MS?  Dr. Racke   You know, for a long time people have been interested in what are the potential targets, and this would represent a little bit different target than the typical myelin proteins that one has thought of as being targets in MS. It’s also kind of interesting because of another molecule, aquaporin 4, that is expressed in the same place in the astrocytic endfeet that’s been the antibody target for neuromyelitis optica. And so I think as we begin to see responses against some of these other molecules, it’s interesting to see whether they result in in demyelination and whether that can be a new avenue for therapeutic intervention.  MSDF   Just within the last week, another study came to a quite different conclusions regarding the prevalence of Kir4.1 autoantibodies in MS. How do you resolve the discrepancy? Dr. Racke   There was data presented yesterday to suggest that one of the differences may actually be differences in glycosylation of Kir4.1. It turns out that eukaryotes—and humans are eukaryotes obviously—glycosylate proteins, and that very often glycosylated protein looks very different to the immune system than an unglycosylated protein. And since a lot of these studies take an unusual cell type and then try to over-express to your 4.1 on its surface and then see whether an antibody recognizes it, it may not be the same type of glycosylation that’s actually seen within patients with MS. MSDF   There’s a lot of research going on now on Kir4.1. What more needs to be done in this area before Kir4.1 becomes a therapeutic target?  Dr. Racke   Right. Well, so, for example, if you look at neuromyelitis optica, that if you did plasmic change in those patients, then very often those patients are benefited. So it’s as though if I take away those antibodies the patient does be better, so those antibodies are pathogenic. When that’s been done in MS, the data, it’s sort of been, I don’t want to say controversial, but in some sense it is. And then there have been studies, for example, done from the Mayo Clinic that looked in at certain types of demyelinating events where it seemed like plasma exchange did work, then there were larger studies that were done and it didn’t seem to work. And if, in fact, it’s, say, a pa a patient population where really only one-third to half of the patients have the pathogenic antibody, then if I do that study and say I’m going to do it to everybody, it may not have enough power to suggest that there’s efficacy for everybody. But I think it gets back also to this idea of what a lot of people talk about in personalized medicine, right, and the idea may be that you would be able to identify patients that perhaps had an antibody to Kir4.1, and then perhaps they would be more amenable to therapeutic interventions that targeted antibody synthesis in the blood. MSDF   Do you think that interventions targeted at Kir4.1, would that would it work much the same way as other as existing therapies in decreasing the number of relapses in re relapsing-remitting MS? Dr. Racke   For example, if you look at things like interferon, natalizumab, the way those therapies are trying to work isn’t against the specific antigen, right. What they’re really trying to do is just interrupt the disease process. And I think the difference is going to be there have been some studies where people were trying to target the specific epitopes to either myelin basic protein – the altered peptide ligand studies were like that – and there’s studies now also where people have solubilized MHC molecule that has a myelin peptide on it. And those are specifically trying to target the immune response against a very specific antigen. Now I have to say that most of those things haven’t really worked very well, and I think part of the reason is that the human immune response is complicated enough, but by the time a person has had several attacks in MS, they probably are making an immune response against a number of myelin antigens, and so if I target just a single antigen it may not work. And that may also end up being true in in terms of Kir4.1, that it’s just going to be another thing. But, I mean, if there’s enough similarities between it and some of the things that we’ve seen with neuromyelitis optica in aquaporin 4, like I say, there the plasma exchange and targeting the B-cell response in many instances has been quite beneficial to pa patients, right. And so I think that’s going to be an important next step to not just demonstrate that it can be part of the target that happens in multiple sclerosis, but whether inhibiting that response to that target actually has therapeutic benefit.    MSDF   You just outlined one area of research on Kir4.1 that needs to go forward. What are some others? Dr. Racke The other issues have to do with trying to understand exactly the cell-type specificity in terms of glycosylation, trying to understand why is it that this particular channel is a target in MS, then are other channels also targets in MS. This sort of opens up a whole other ballgame in terms of diversity of targets that could potentially participate in MS pathogenesis. MSDF   Is there anything else you’d like to add about Kir4.1 that we haven’t already talked about? Dr. Racke   I’ve been in this field for 20 years, and realistically this has been the first new antigen that really has come up. And that’s sort of interesting in and of its own right. I think the other thing, obviously, for those people who are interested in things like molecular mimicry, this gives you another molecule to begin to look at in terms of its sequence homology with infectious agents. I mean, the people who are interested in, you know, viruses like HHV-6 and Epstein-Barr viruses, and those that they think that have an important role potentially in MS pathogenesis, how might infections with those agents affect Kir4.1 expression. That’s going to be another area that’ll be of interest to the research community in MS. MSDF   Well, Dr. Racke, thank you very much.  Dr. Racke   You’re welcome.  [transition music]   Thank you for listening to Episode Four of Multiple Sclerosis Discovery. This Podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the nonprofit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is Vice President of Scientific Operations.    Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.    We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to [email protected].    [outro music]