Multiple Sclerosis Discovery -- Episode 5 with Dr. Anne Cross

[intro music]   Host – Dan Keller  Hello, and welcome to Episode Five of Multiple Sclerosis Discovery, the Podcast of the MS Discovery Forum. I’m your host, Dan Keller.    This week’s Podcast features an interview with Dr. Anne Cross, who reflects on the past year in MS research. 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 have discovered that multiple sclerosis may have something in common with colon cancer; the Wnt pathway. It’s a genetic pathway important in development, stem cell maintenance, and cell differentiation. In colon cancer, the mutation of a mediator gene called APC causes the Wnt pathway to become overactive, leading to tumor formation. Now, researchers have discovered that a loss of function mutation of APC in the brain also leads to an overactive Wnt pathway, ultimately freezing oligodendrocyte progenitor cells in their undifferentiated state.    Next, what disease-modifying therapies should women start or stop before pregnancy? In our latest news synthesis, we discuss the difficulties many women with MS have in deciding when to stop DMT before trying to conceive. Since it can take months, and even years, for a woman to conceive, it’s important that she spend the least amount of time off medication as possible to reduce the chance of relapse. Some drugs may be worth taking during pregnancy anyway, but it’s up to the neurologist to do a risk-benefit analysis for each patient. Nevertheless, many women opt to go off of DMT altogether to reduce the risk of adverse effects on the fetus.   Finally, we would like to direct your attention to funding opportunities on the MSDF webpage. Under the Professional Resources tab at msdiscovery.org, you can find a listing of various organizations offering funding for research grants, fellowship grants, and more. Currently, there are several opportunities offered from ECTRIMS with deadlines this winter. There are also several deadlines for funding from the National MS Society coming up in August.    Now for the interview.   Interviewer – Bob Finn This is Bob Finn. I’m here with Dr. Anne Cross of the Washington University in St. Louis. Dr. Cross will later today be giving a talk at the American Academy of Neurology meeting on what the year has been like in MS research. And, so, let me ask you briefly, what has the year been like? Has it been a good year, a bad year, an exciting year, a boring year?   Interviewee – Anne Cross  I think it’s been a pretty good year. There have been some mainly good things, a couple of bad things, some rather interesting and unexpected things, too. I guess some of the good things involve genetics research papers that have come out identifying genes that are associated with risk of developing MS. That’s been kind of exciting. Actually, there were 48 new genes that were identified and published this year by the International MS Genetics Consortium, which is a very large group of international researchers that have amassed probably close to 30,000 genetic samples from MS patients over the years that they’ve been in existence, which is about 10 years, plus close to double that of controls. And all these MS patient samples are from patients who were well characterized and submitted by, generally, MS specialists.    And that group did a study using something called the Immunochip, which is a genotyping array that was actually developed by a group of investigators who work on autoimmune disorders, so that array is very much weighted towards beings with immunologic function. So not too unexpectedly, all 48 of the newest identified genes all relate in some way to the immune system or are very closely linked to genes of immune function. But prior to that, the same group – the International MS Genetics Consortium – had identified about 50, a little over 50 genes that are associated with MS risk, and most of them were also related to genes of immune function. So I think together, all of this data certainly implicates the immune system, which we already knew, but I think things are certainly solidifying around that with the newest data.   MSDF  Let me ask you, if they’re using techniques that are specific for immunological genes, are they missing other genes?   Dr. Cross  They very well could be. The original studies that this group did which were published, the biggest study was published in the summer of 2011, did not do it in that fashion, though, they just did a genome-wide association study, and most of the genes that they identified were related to the immune system directly or indirectly. So, yes, I’m sure that some are being missed that aren’t related to the genes that are on this Immunochip microarray, but they’re trying to hone down a bit.    And some of the other things that were discovered were that, well, they identified 5 allelic variants; the particular allelic variant was over 50% of the time associated with risk of MS. And they also identified in this latest search – well, the strongest association was with a gene that has immune function called Vcl-10 – they actually in this latest search rediscovered the same 50 or so that they had discovered before, so they were actually mostly in this Immunochip microarray.   MSDF  So, aside from the genome-wide association studies, what else has been interesting in MS research this year?   Dr. Cross  Well, I think some of the clinical trials that have been published in the past year, and also that are just ongoing and aren’t published yet, have been interesting. This past week, Dr. Rhonda Voskuhl, who’s from UCLA, spoke and presented for the first time ever recent data from a study of estriol, which is a pregnancy hormone that was added to glatiramer acetate in women with relapsing-remitting MS, and that was compared to placebo pills added to glatiramer acetate. And the results were pretty positive, especially in the first year when there was an almost 50% reduction in relapse rate in the group that received estriol plus glatiramer. And, you know, that’s, of course, based upon longstanding data that we’ve known, that women with MS who have relapsing disease have a much decreased relapse rate during pregnancy. And then Dr. Voskuhl had done a good bit of work with estriol, in particular, which is a fairly safe pregnancy estrogen hormone compared to some of the others, but it’s not available in the United States right now.    MSDF  You mentioned that there were some disappoints.   Dr. Cross  At least for me, and probably for a lot of MS patients, the biggest disappointment was the failure of the FDA to approve a drug called alemtuzumab, which is a humanized monoclonal antibody against an antigen that’s on pretty much all the mononuclear cells of the immune system. And the US FDA failed to approve it, although, I believe, 32 countries and counting have approved it at this point, including Canada and Mexico and all of the countries of Western Europe, Australia, Brazil.   MSDF  Have there been any interesting developments on the remyelination front?   Dr. Cross  Yes, yes, yes. In fact, I hope to speak about that today. There are studies in early-phase trials right now of anti-LINGO-1, which is a humanized monoclonal antibody against a molecule called LINGO-1, which is found only in the central nervous system – at least that’s what the data says so far – and it’s expressed by oligodendroglial cells, or the cells that make central nervous system myelin. And, for whatever reason, it’s involved in inhibiting remyelination in the central nervous system. So the monoclonal antibody that inhibits it then enhances remyelination. And in mouse models it looked very good, and it also led to less injury to axons, or nerve fibers, so it had more than just a remyelinating effect. And it’s now in phase II studies in relapsing-remitting MS and optic neuritis patients. At least the relapsing-remitting MS study is fully enrolled, and so we’ll be looking forward to those results.   So another potential remyelinating agent is a little bit behind anti-LINGO-1. It’s called recombinant human IgM22, and it was developed from a natural IgM antibody that was discovered at Mayo Clinic that binds to a surface antigen on oligodendrocytes – the cells that make central nervous system myelin – and it enhances myelination in mouse models of demyelination, and, in fact, in some studies, just a single dose of that led to longstanding remyelination in the mouse model. So that’s in dose-finding studies in human beings at the present time, and hopefully will move forward from there.   Other exciting things, at least to me, are studies of stem cells that can be differentiated into different types of cells. And, at this point, you can actually take human skin cells or human fibroblasts and revert them back to stem cells; they’re called induced pluripotent stem cells. So you can actually take a person’s skin and do that, and then you can differentiate it forward into whatever cell type you want, really, these days; I mean, you can differentiate them into neurons. And in MS, we’re very interested in differentiating them into oligodendrocyte precursor cells – cells that form the cells that make central nervous system myelin.    And a study that I plan to talk about this afternoon took such cells and made them into human oligodendrocyte precursor cells and put them into the central nervous systems of mice who had a genetic mutation in myelin basic proteins, so they are essentially unmyelinated. And these mice die very soon after being born, much earlier than normal, and they put these human cells in. They had to immunosuppress the mice so that they’d accept the human cells. But these cells actually made myelin, and it was functional myelin at least from the standpoint of wrapping around fairly normal-looking nerve fibers, axons, from the mice, and forming compact, normal-appearing myelin. So that particular group, they’re from New York State and they’re affiliated with several other medical centers, and they plan to get this into humans pretty soon. Their first project, however, is going to involve fetal stem cells first, because that was easier to get approved and moved forward on, and so I believe they’re already funded to do a three-center – all in New York State – stem cell study injecting such cells into the central nervous system of people with secondary progressive MS.    MSDF  Now some patients aren’t waiting for the studies, I understand, but what is your point-of-view about that?   Dr. Cross  It depends on where they’re going and what they’re doing. I personally think there’s some shoddy research, some charlatans you might call them, out there who are taking the money and presenting false hopes to patients that I certainly disagree with. And I have one particular patient I know who went to another country and had stem cell therapy done in what she described as a very dirty environment. And luckily nothing bad happened to her from this experience, but nothing good happened either. I’m hoping that she’ll be able to get into some of these well-done, scientifically valid, protocol-driven studies that seem to have some promise.    MSDF  Any other interesting areas of MS research in the past year?   Dr. Cross  I think the unexpected finding that I plan to talk about is an association of salt – sodium in particular, the sodium component of sodium chloride – in the development of a particular type of pathogenic T-cell that at least is related to the mouse model of MS called experimental autoimmune encephalomyelitis. These are Th17 cells and they’ve been shown to, at least in some models, cause the EAE model for MS. And it was found that if you increase the salt intake of mice that had been induced to develop this model and compared them to mice who weren’t getting extra salt in their diet, that the mice who got extra salt got disease earlier; they had a more severe course, they didn’t recover as well, and they had histologically when you looked at their central nervous systems, more cells infiltrating and just more damaging. So that was kind of interesting and quite unexpected, I would say.    Two different groups of investigators sort of came up with that at the same time; I’m sure they were speaking to each other about it, that the studies came out right together. It certainly would be a modifiable environmental thing if it proves to be true, and perhaps even a little bit simple. And there is actually a scientific reason behind why this might occur. Well, there’s a response in the body by something called p38 MAP kinase in response to, like, many different stresses, but including among them osmotic stress which increased salt could cause. And that pathway that p38 MAP kinase is involved in eventually can lead to the induction of a particular kinase that is key to the development of Th17 cells. So it sort of all, you know, fits together.    There are certainly some things that don’t fit with that. I think that certain areas of the world, for example, have very high salt intake and yet have low MS rates, but it may be that there’s this environmental factor. There probably are many different environmental factors that’s going together with a genetic predisposition, and those together are probably leading, perhaps, to MS. In any event, this will have to be proven by other groups, but if the association is true, it would certainly be modifiable.     MSDF  So looking ahead into the next year of MS research, what are you particularly looking forward to seeing?   Dr. Cross  I’d like to see more data come out on some of the other oral agents; there are a couple that are in the pipeline that are being looked at that perhaps have other mechanisms of actions from what we have now. I’d like to see other studies funded for estriol so that perhaps it could come to the United States and be an adjunctive therapy probably for women with MS and probably pretty safe. I’m really hopeful – I’m not sure if it’ll be in the next year – that we’ll see some good data coming out from these scientifically valid stem cells projects to help people with progressive MS, and help people who have longstanding disability to recover some function; those are the people that really, really need help in the MS world right now.   MSDF  Well, Dr. Cross, thank you very much.   Dr. Cross  Thank you.   [transition music]   Thank you for listening to Episode Five of Multiple Sclerosis Discovery. This Podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the 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]