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Multiple Sclerosis Discovery: The Podcast of the MS Discovery Forum

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Now displaying: January, 2015
Jan 26, 2015

[intro music]

 

Hello, and welcome to Episode Twenty-Nine of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.

 

This week’s podcast features an interview with Dr. Monica Carson on funding research in MS. But to begin, here is a brief summary of some of the latest developments on the MS Discovery Forum at msdiscovery.org.

 

Glatiramer acetate and the interferon betas appear to be clinically similar, according to a new study in the Multiple Sclerosis Journal. This study follows on the heels of a Cochrane meta-analysis we covered earlier in 2014 that found similar results. Instead of performing a meta-analysis, though, the researchers of the MSJ article used data from over 3,000 patients in the MS Base database. They found very little difference in annualized relapse rates over 10 years, though glatiramer acetate and subcutaneous interferon beta 1-a did eke out a statistical win over the other interferons.

 

Together, MSDF and our non-profit publisher, Accelerated Cure for Multiple Sclerosis, are committed to speeding the pathway toward a cure for MS. Among the news and resources we provide is a list of more than two dozen tissue repositories, including one maintained by Accelerated Cure. Visit our website and click on the “tissue repositories” button under the “research resources” tab to browse through repositories from all over the globe.

 

Another part of our goal in working faster toward a cure is to provide a place where researchers can share their experiences and expertise with one another and also debate controversial issues in MS research. We encourage researchers and clinicians from all disciplines to log onto our forum and discuss their latest research, techniques, and discoveries. We also encourage you to help keep us up-to-date on your latest work by e-mailing us directly. Send information you’d like to share on job postings, meetings, funding opportunities, or other news to editor at msdiscovery.org.

 

[transition music]

 

Now to the interview. Dr. Monica Carson is director of the center for glial-neural interactions at the University of California, Riverside. She met with MSDF editor-in-chief, Bob Finn, to talk about the current state of funding in MS research.

 

[Interview]

 

Interviewer – Robert Finn

Dr. Carson, welcome.

 

Interviewee – Monica Carson

Thank you.

 

MSDF

So let’s stipulate that there’s never enough money available for funding any area of research adequately. On a scale from bad to awful to dire, what is the state of funding for MS research?

 

Dr. Carson

I would say it’s better than maybe other areas, but all areas of research, I feel, are dire, so I do not want to make MS research sound worse. It’s probably actually better because individuals can see the value of research in disease-oriented research programs. So in a worse situation, it’s good.

 

MSDF

So there are essentially three sources of research funding. There’s the government; there are nonprofits; and then there are for-profit companies, mostly pharmaceutical companies in the biomedical area. How are each of these doing in funding MS research?

 

Dr. Carson

There are objectives in all of these. There’s always been a long-term funding priority in NIH NINDS. There’s also out of various objectives that are perhaps nontraditional for those of us who came up as NIH-funded investigators, such as the DOD and various congressionally-mandated research programs. There are much more funding, I think, also in private foundations. Funding in biotech and pharmaceutical, I think, has been the one area that has dropped severely over the years, and that one is not an area that I think one can count on, that is going to be something targeted when you have a proposal. And then you do have to work through the ethics and various other aspects of that.

 

That said, the National Multiple Sclerosis Society has really shown a very nice model of partnering with pharmaceuticals with their Fast Forward program. I’ve served on those panels and they are really wonderful models of projects that are brought in that have sufficient IP – intellectual property – protection of the ideas brought in that could be moved Fast Forward by a partnership with pharmaceutical and the National Multiple Sclerosis Society. So there are targeted areas, but of course it’s going to be very more modest in general funding overall for the average investigator, whereas the more traditional governmental and private foundations are going to be our primary sources.

 

MSDF

How do you account for the drop-off in pharmaceutical company funding?

 

Dr. Carson

Well, I am not an expert in economics, in the costs that it takes to take something to market, but I would speculate that it has to do with the difficulty of getting drugs that work in the brain that pass all the various measures of blood-brain barrier, unexpected toxicities and side effects. And so I think this area of pharmaceuticals has had great expense but great dropouts. So for great expense there hasn’t been a lot of drugs coming out except in targeted areas. I would say recently it’s been very exciting about the therapies that are coming out in MS research.

 

MSDF

So do these three sources – government, nonprofit, for-profit – do they tend to support different types of research?

 

Dr. Carson

Yes, very much so. I think as we very much know, you go to NIH, it’s a good scientific idea, needs to impact health, could be a basic science issue that applies to MS but also might apply to Alzheimer’s diseases, neural inflammation, or a variety of other diseases in childhood. When you get to a private foundation, the private foundation has taken donations or raised money very specifically for a disease, and so different private foundations are going to be focused on how much other research is applied to the disease, but also how translational it is. How important that translational element is going to be specific to the different foundation. But all of the private foundations are going to be very specific that this is not just a good idea, but is a good idea for their diseases, specifically multiple sclerosis.

 

MSDF

So let’s say you are a researcher, possibly a young researcher, searching for his or her first research funding. How do you strategize the search for research funding?

 

Dr. Carson

Very good question. I don’t think there’s one right answer to this and one has to look at one’s own portfolio of research, one’s resources, and what one can actually deliver after one has made a promise in a grant proposal. And I think you need to as a young researcher get advice from senior researchers and investigators in your area in your field to see how to go forward. But very often the best way is to take advantage of the pilot grants, the junior investigative grants that are really targeted to getting you off the ground and can have ideas that are high-risk, high-impact.

 

There are also many of these pilot grants from the private foundations, such as the National Multiple Sclerosis Society has a pilot project; it’s aimed at getting folks to get their early funding in MS to sort of capture them as a long-term MS researcher. So I think the pilot grants are a good way to start to get that bolus of research-funded publications, demonstrate your productivity level so that you get the larger grants from NIH.

 

MSDF

So let’s talk specifically about the National MS Society and Erase MS, which are the two large nonprofits that you’ve been involved with. How do their funding philosophies differ?

 

Dr. Carson

Well, I’m not really ready at this point to talk quite about more about the Erase MS, because I’ve just joined their scientific advisory board and I am about to start participating in their review cycles. And so I think it’s best to go through that cycle a few more times before commenting on that. But I would say it’s going to be very focused. They are also looking at bringing together research centers, and the Erase MS is very much focused on therapies and things that are going to move things forward quite fast. So in that sense, the MS Society is a more longstanding society; it has been on my mind one of the best models of collecting money, giving out money to researchers, making sure the research is very specific to MS. And this goes back to my prior point. Having been on MS study sections, it’s very important for them – this can’t be just a good idea – it has to be applying to MS.

 

So one of the things I think is the other very big difference between these is the MS Society also has a lot of different types of grant funding programs – these pilots which I just mentioned; training grants; transition grants which are very important to the junior investigator which will take you being from a senior post-doc to an independent position; as well as larger grants, 3-year grants, that are sufficient to carry a major project.

 

MSDF

So there’s a perception in the public, I think among scientists as well, that some of the big disease societies spend 90% of their funding on administration and 10% on funding research. How does the National MS Society stack up in that regard?

 

Dr. Carson

I would say the MS Society is a model of what most disease societies should be. I have been impressed by them from when I entered the research field starting off in MS and being funded – so just for conflict of interest, I was funded at 5M as a post-doctoral fellow – and what I have been impressed because I have had colleagues, I have had neighbors who develop MS or children who have MS, so I’ve seen it from both sides. I am very impressed how they keep a very lean, mean administration, they keep reinvestigating how they should be distributing the money.

 

They think about how much of the money is really going toward patient causes, as things about wheelchairs and thinking about those things, but also in the research; what’s the right time and how much to give the pilots to just generate these, you know, high-risk but potentially high-impact projects and keeping the money small. They look at things for these transition awards to really capture people when they saw that this was a dropout period that people were trying to have a problem launching. They are the ones when you are trying to get that NIH grant and you’ve been a successful investigator, they are focused on MS and they get these nice, shorter three-year grants. And they are very focused. And sometimes if you’re thinking it may be a little too harsh, but saying that it’s MS-focused.

 

So if you are somebody who’s a donor, you should be very happy with the money that you’re giving. And they’re constantly reevaluating the distribution of the dollars, the impact, and, hence, they came up with the Fast Forward. How do they facilitate the problem of pharmaceuticals not bringing enough drugs to therapies, how could they aid this process? Hence, fast forward; trying to bring in nice grants, innovative grants, linking them up with pharmaceuticals to move things forward. So, in a nutshell, they are very milestone oriented not to keep being their own operation alive, but they can’t cure MS to make your life with MS as palliative. You have as much retention of your motor and other capabilities and that you can arrest disease process and perhaps reverse it. So they are very milestone oriented, and I’ve had high respect for how they keep re-self-examining the organization.

 

MSDF

Well, I’ve come to the end of my prepared questions. Is there anything that I haven’t asked about MS research funding that I should have asked, or anything you’d like to add?

 

Dr. Carson

I wouldn’t be afraid of entering the field because of the funding. I think there are multiple ways to have funding. And sometimes you won’t go through the traditional MS societies, sometimes it’ll just be a great idea and you’ll find some other kind of innovative idea. And the last thing I would say that you haven’t asked is that we’re past the time of being the lone-wolf researcher; it really is time to come together, as we have at the symposium here, is taking diverse experts, coming together and melding together projects. These are the ones that are going to be the most competitive in a sense, not only of getting funding, but if we’re really looking at curing diseases, are the most likely to stand the test of time with the diversity of opinions and eyes looking at the problem.

 

MSDF

Dr. Carson, thank you very much.

 

Dr. Carson

Thank you.

 

[transition music]

 

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

 

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

 

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

 

 [outro music]

 

Jan 20, 2015

[intro music]

 

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

 

This week’s podcast features part two of an interview with Dr. Brenda Banwell in which we discuss pediatric MS. But to begin, here’s a brief summary of some of the latest developments on the MS Discovery Forum at msdiscovery.org.

 

Researchers recently put a simple measure of corpus callosum atrophy to the test in a 17-year-long study. The team measured the area of this inter-hemisphere highway in MS patients and found it correlated with their cognitive and physical disabilities over time. Corpus callosum area is faster, easier, and cheaper to measure than volume, since it requires no special equipment beyond the typical MRI machine. The researchers hope they will be able to demonstrate that this measurement can also predict disease course in future studies with larger cohorts.

 

Every Friday we curate research articles on all topics related to multiple sclerosis and highlight our favorites in the “Editors’ Pick.” Two weeks ago, the editors’ picks included a study on the HPV vaccine and MS and another about how cinnamon can ameliorate EAE. Last week we chose a study on heterogeneity among oligodendrocyte precursor cells and another on teasing out the causal variants in genetics association studies. You can see our weekly picks by going to our website, clicking on the “Papers” tab, and selecting “Editors’ Picks.” In addition to the Editors’ Picks, we link to every MS-related study found in PubMed.

 

Our senior science writer, Carol Morton, will be at the Keystone meeting on Neuroinflammation in Diseases of the Central Nervous System in Taos, New Mexico from January 25th through the 30th. She will be on the hunt for good stories and interviews for this podcast, so be sure to say “hi” and tell her all about your latest work.

 

[transition music]

 

Now to the interview. Dr. Brenda Banwell is Professor of Neurology and Pediatrics at the Perelman School of Medicine at the University of Pennsylvania and chief of the Division of Neurology at The Children’s Hospital of Philadelphia. Last week, we talked about a new journal called Multiple Sclerosis and Related Disorders, of which she is one of the co-editors-in-chief. This week we turn to her particular subspecialty.

 

[Interview]

 

Interviewer – Dan Keller

I’m here at The Children’s Hospital of Philadelphia with Dr. Banwell, and someone from the public affairs office is here with us. Dr. Banwell, let’s talk about pediatric MS. What are some of the clinical features that you see that may distinguish it from adult?

 

Interviewee – Brenda Banwell

Maybe walk you through a little bit of the journey that the pediatric multiple sclerosis field has taken over the last 10-12 years. When pediatric multiple sclerosis clinics were first being created which was in the late 1990s, the literature on pediatric multiple sclerosis was extremely brief; it was a mixture of patients that we now recognize have multiple sclerosis, some have what we call acute disseminated encephalomyelitis – ADEM – and still others had different demyelinating disorders. And there were no consensus criteria for the diagnosis of multiple sclerosis in children and the criteria for the diagnosis in adults did not include pediatric-onset patients formally. All of that has changed. And in the process of making the diagnosis of multiple sclerosis more clearly, we obviously had to look at the clinical features.

 

So, first of all, I would say that multiple sclerosis onset during childhood and teenage years is relapsing-remitting in character, so clear relapses and periods of clear remission. We have not seen children with primary progressive multiple sclerosis. Worldwide there are a very, very small number of children who may have that diagnosis; it’s extremely unlikely that there are very many, so for all intents and purposes it’s a relapsing-remitting disease during the pediatric age group.

 

The clinical features of attacks are generally very similar to adults with a few caveats. In children who are under about 10, there’s a likelihood that the children will present a little more atypically than adults. The younger children present with an episode with multiple neurological deficits, confusion, even impairment in level of consciousness which can make that first episode very difficult to distinguish from the more traditional acute disseminated encephalomyelitis, the important difference between the two being acute disseminated encephalomyelitis is a monophasic disease, so one attack almost always without any MRI evidence of new disease over time and no further clinical relapses in the vast majority of those children. So it’s a very important diagnosis to distinguish from the lifelong disease, multiple sclerosis, and one can distinguish them obviously on the basis of time but also on certain MRI features. And specifically when one looks at the first presentation, looking for risk determinants for multiple sclerosis are also important.

 

So in that vein, we’ve looked at things that are associated with the likelihood that a first attack is really multiple sclerosis, and those include prior exposure to Epstein-Barr virus, which gives one about a sixfold increased likelihood of having MS; low vitamin D levels which is a problem because low vitamin D levels are quite common in the community now across the board in certain parts of the world, but children who have very low levels are more likely to have multiple sclerosis compared to children whose vitamin D levels were higher when they present with an acute event.

 

If the MRI scan in the brain shows areas of what we call “T1 hypointensity”, which are black holes or really are indications of focal prior brain injury, then those patients are much more likely to have multiple sclerosis. And the reason for that is that in multiple sclerosis, the first attack when you first have the deficits, there’s likely been a period of time behind the scenes where the immune system has begun to attack and has had focal areas of injury that the patient didn’t recognize but are clearly visible on MRI, so MRI is our extraordinarily helpful guide. So areas of abnormality in the brain that are in the what we call periventricular white matter, and then these dark areas on these what are called T1 sequences are strongly indicative that this is a first attack of multiple sclerosis.

 

Conversely, most children with transient illness either have a normal brain MRI and maybe have inflammation in the back of the eye, the optic nerve, or the spinal cord, or they have this ADEM – acute disseminated encephalomyelitis picture – which gives you these hazy, widespread, large, ill-defined changes in the brain MRI that are at least visually quite different from multiple sclerosis. The key subsequent to that is that in patients with multiple sclerosis, by definition there will be new disease over time both on serial MRI scans and clinically. And that is also the case in young adults with relapsing-remitting multiple sclerosis.

 

Genetically, pediatric MS patients do have – at least those from northern European heritage – a higher likelihood of having what we call the HLA-DRB*1501 locus, which is a gene that is important in immune system development or at least immune system recognition of self. And that relationship is true in adult-onset MS as well, and over the last few years the number of genes that have been linked to multiple sclerosis risk overall, and that panel of genes is similar in pediatric-onset MS.

 

So I think the overall message is that relapsing-remitting multiple sclerosis in children and adults is very likely to be the same disease. There are some subtle differences relating to the age of the patient, but if you follow people over time the relapsing-remitting character and the changes on imaging and these clinical feature of kids are really quite similar to relapsing-remitting MS in young adults.

 

MSDF

When you mentioned exposure to Epstein-Barr virus as a risk factor, if you looked at adults about 90% of people have antibody. Do kids generally not have such a proportion of antibody and it’s more indicative there? Does it tell you more if they are positive than in an adult?

 

Dr. Banwell

There’s a lot of evidence that suggests that your multiple sclerosis risk is determined by where you grow up in your childhood years. You may not manifest with the disease until you’re 20 or 30, but all sort of studies, particularly immigration studies, strongly suggest it’s where you grow up that determines your risk. Therefore, if something is a risk factor, one ought to have it if your onset is a 6-year-old or an 8-year-old or a 10-year-old, if it’s important in causing the disease. So when we looked at Epstein-Barr virus exposure in pediatric-onset MS patients, about 80-85% are positive, which compares to only about 35-40% of regional, age, and sex-matched healthy children. So our power to make the relationship is very high. What the Epstein-Barr virus means to the person may be very similar in kids and adults. Certainly in adult-onset MS patients, about 97-98% are positive, which compares to about 90% of the healthy population. So it’s still higher but, of course, you’re sampling the adult patients way past when the exposure may have occurred, and so there’s been time for people who don’t have the disease to also experience the exposure, it just doesn’t matter – presumably – to them; they’re not manifesting with MS.

 

In children, though, when we’re looking at patients who are presenting very, very close to when they presumably had the key risk exposure. So we think that’s biologically important. We’ve also looked at viral shedding. So Epstein-Barr virus is an interesting infection because once you acquire it, it lives in your B-cell population so you have EBV-infected B cells, and about 20% of the year you shed the virus in saliva, which is why it’s so easily spread, particularly in adolescence, which is when it’s particularly acquired. So we looked in our pediatric MS patients at how many times in the course of a year, so with a sample done with most swabs once a month, were they shedding the virus, and looked at Epstein-Barr virus-exposed healthy kids. Healthy children shed the virus 20% of the year, as has been previously reported; MS patients, it was 66-70% of the year.

 

So one of our hypotheses that we’re currently exploring further is whether maybe part of what Epstein-Barr virus might do in MS is, first of all, shed more often so you’re controlling it less well. Every time you shed the virus, your immune system has to turn itself back on and put the virus back into its latent state. If you don’t you can end up with all sorts of complications including lymphoma. And so if part of Epstein-Barr virus’ role in MS is turning the immune system on multiple months per year, that isn’t probably what you want when you have an autoimmune disease; you don’t want your immune system being turned on multiple times a year, particularly if unfortunately you turn on a component of the immune system that may then be directed at the brain. So that’s an interesting phenomenon that we’re currently doing further research on.

 

MSDF

So it sounds like the EBV is something of a polyclonal activator of B cells which then cross-react in the brain, or do react in the brain?

 

Dr. Banwell

Well, that’s the next stage is to see if you look at what immune cells are responding to the challenge of this reactivated EBV, is it that there are specific T-cell clones, and if so are those T-cells specifically looking at proteins expressed both by EBV and by proteins in the central nervous system, sort of a molecular mimicry model, which might be true? Or is it just unfortunate that you’ve turned the whole immune system on, or a large number of aspects of the immune system on, which is more of a general immune process? We don’t know the answer to that.

 

MSDF

Considering these patients start out with relapsing-remitting MS earlier, do they progress to secondary-progressive earlier or at the same age as someone who gets it as an adult?

 

Dr. Banwell

Good question. So the only really good paper on that question, keeping in mind that if we go from prospective studies that are really only started in 1999 to 2000, we don’t have a lot of prospectively rigorously studied pediatric patients. But Dr. Renaud in the New England Journal of Medicine published a paper from the French database where they looked at patients who reported pediatric-onset MS. And what they found was that from first attack until the point at which 50% of their pediatric-onset patients had started into secondary disease progression, that time interval was about 20 years, which is about 10 years longer than one would report on average in adult-onset MS. So if you look at adult-onset MS patients, 50% of them will have entered into secondary disease progression after 10 years from first attack. This is all untreated patients, which of course now is no longer really much the case in developed parts of the world.

 

So the patients with pediatric-onset take longer to start into secondary disease progression, but if you’re only 6 or 7 or 8 when you have your first attack, you’re 28 when you start to develop disability, which is about 10 years younger than most of the adult-onset patients. So the take-home message is it is certainly not more benign based on this particular data, the age at which patients are at-risk of becoming disabled is actually younger, but the time interval from the beginning of their disease until that time point is longer. And we hope that the current therapies and the new emerging therapies will change that outcome, but of course we only are just beginning to have a chance to see that.

 

MSDF

What are some of the challenges in doing clinical trials with a pediatric population?

 

Dr. Banwell

So in adult-onset MS patients, the clinical trial models have been very large; they’ve been randomized, double-blind, placebo-controlled, rigorously done studies that have often employed 200-400 individuals per study arm. And that is often quite feasible because the large MS programs around in North America and in many parts of Europe, an average adult MS clinic where MS is a common can have 3,000 patients alone. There are probably fewer than 3,000 pediatric-onset MS patients available for clinical trials worldwide total, and even that number may be inaccurate. So most pediatric MS programs in the world, of which there are still relatively few that have anything more than five or six patients, are really, really few and far between. So there just simply is a markedly reduced number of pediatric MS patients available for clinical trials.

 

Also challenging the current environment is that there are multiple trials all coming forward at the same time. So the FDA and the European’s Medicine Agency in particular require what they call “Pediatric Investigation Plans” – or PIPs – for all new drugs that are coming to market. In the MS field there are multiple new drugs coming to market. All of them have filed these Pediatric Investigation Plans. So even if we had the number of patients to power one study, we certainly don’t have enough patients to power five or six concurrently, therefore we run the risk of a given trial failing because it doesn’t reach its enrollment numbers.

 

We have families facing choices between multiple potential clinical trials at the same time and centers facing the challenge of launching multiple trials at the same time and the inherent difficulty with all of the work that goes into getting a study up and running at a given center. Pediatric MS patients have never previously been offered pediatric trial opportunities, so the culture of being in a trial is new so it’s a learning curve for everyone. And the medications that are being put forward have varying priorities. So some of the medications are oral, which may be quite appealing to children who are not, understandably, very keen on injections; some are given by infusion and that has varying challenges.

 

A clinical trial is not just an enormous time commitment on the behalf of the patient, in which our case is a child, but also their parents who have work and other commitments and other children. So being part of a clinical trial is an enormous commitment for a family, which is different than the commitment experienced by an individual who’s making that decision on their own behalf. And then adding to all of those challenges is the safety aspects of all these new medications, and of course our top priority amongst anything else is to make sure that our patients stay safe.

 

And so where there may be marked similarity in relapsing-remitting MS as a disease between children and adults, these therapies are being administered at a different time in terms of brain maturation, to a lesser worry but still important in terms of different levels of immune maturation, and certainly – very importantly – at a different stage of life in terms of acquisition of infection. And so many of the new medications that are coming online are more powerful than the medicines that are currently available, many are more capable of suppressing immune responses which puts a significant burden on making sure that everybody is fully vaccinated to the various things we can vaccinate against, but still kids are going to acquire their first infections during the window of time they may be on some of these medications. And so it’s really quite similar to some extent to some of the pediatric oncology care plans that we have to be very, very aware of.

 

MSDF

It looks like the Canadian database of pediatric MS patients is one of the largest; I think when I talked to Amit Bar-Or, it was about 420 or 450. It sounds like there’s a real vying here for patients in terms of clinical trials, and is it even feasible; is it something that you should just discuss with the FDA and say how is this possible to do?

 

Dr. Banwell

So I am one of four members of a clinical trials advisory group on behalf of the International Pediatric Multiple Sclerosis Study Group, which is an international group of about 150 physicians from 40 countries, so I do serve on an advisory to FDA and EMA under that umbrella. And the group of us have very much expressed this concern to FDA and EMA and have articulated our worry about underpowered trials. It’s a difficult environment, there’s a lot of discussion still to be had. The general statement from the regulatory authorities for each of the individual medications that are coming forward is that they are required to have a pediatric plan. And that was a hard-fought battle over many years to try to increase high-quality evidence for treatment of children, which all of us who treat children endorse.

 

So it’s not that we don’t want there to be good trials, it’s just, unfortunately, the reality is that it’s going to be very difficult to do traditional study designs with large arms and placebo-controlled, randomized, double-blinded models are not always going to be suited for all of the therapies. They’re not possible to do for every therapy that’s coming forward, and there’s going to need to be some discussion at a minimum on trial design and potentially on which trials are being done in what order, although that, of course, is certainly not my purview to decide, but it isn’t feasible to run multiple trials in this rare disease at the same time. So we’re going to need to look at rare disease models of therapy that have been put forward for perhaps some of the rare childhood cancers, for example, and other diseases, and we’re going to need the regulatory authorities to recognize we can’t use adult MS study designs for pediatric MS patients.

 

MSDF

Very good, I appreciate it. Thank you.

 

Dr. Banwell

Oh, you’re welcome.

 

[transition music]

 

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

 

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

 

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

 

 [outro music]

 

Jan 12, 2015

[intro music]

 

Hello, and welcome to Episode Twenty-Seven of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.

 

This week’s podcast features an interview with Dr. Brenda Banwell about a new journal on multiple sclerosis and related disorders, of which she is a co-editor-in-chief. But to begin, here’s a brief summary of some of the latest developments on the MS Discovery Forum at msdiscovery.org.

 

This week we published two stories related to articles published in the December 2014 issue of JAMA Neurology. The first article is about the interim results of the Halt MS trial. In this phase 2 clinical trial, physicians performed autologous hematopoietic stem cell transplants on 24 patients with relapsing-remitting MS. In other words, the team obliterated the patients’ existing immune systems and attempted to hit the reset button by infusing the patients’ own stem cells. Three years after the treatment, 78% of patients showed no signs of disease activity, significantly higher than similar studies using conventional MS treatments. However, not everyone is popping the champagne yet. Some are concerned that the treatment may not have been aggressive enough to eradicate the patients’ entire immune systems, and it will be only a matter of time before some patients start showing signs of disease activity once more. Others are concerned that the treatment was unnecessarily intense and risky, suggesting safer methods of stem cell transplant would be effective in resetting the immune system.

 

Halt MS is one of the trials using a new primary outcome measure called “no evidence of disease activity” or NEDA for short. NEDA is basically a fancy way of saying “remission”; that is, no relapses, no disability progression, and no new lesions on MRI. NEDA sets a new treatment standard for patients and their doctors, reflecting the hope of a new generation of disease-modifying therapies.

 

But is NEDA really a feasible clinical care target? Our second story this week takes a look at this issue with the first real-world cohort study. Researchers asked how many people with relapsing-remitting MS maintained NEDA status seven years after diagnosis. While that goal remained elusive for all but 8% of patients, NEDA status at two years was highly predictive of no disease progression at seven years. Many questions remain about NEDA. But in an editorial accompanying the study, researchers suggest that NEDA is still a worthy, albeit very ambitious, goal.

 

What do you think? Let us know on the discussion forums at msdiscovery.org/forums/discussion.

 

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Now to the interview. Dr. Brenda Banwell is Professor of Neurology and Pediatrics at the Perelman School of Medicine of the University of Pennsylvania and is chief of the Division of Neurology at The Children’s Hospital of Philadelphia. We met to talk about a fairly new journal called Multiple Sclerosis and Related Disorders, of which she is one of the co-editors-in-chief.

 

[Interview]

 

Interviewer – Dan Keller

I’m here at The Children’s Hospital of Philadelphia with Dr. Banwell, and someone from the public affairs office is here with us. I’m just wondering why did you see a need for a new journal?

 

Interviewee – Brenda Banwell

At the time that we launched Multiple Sclerosis and Related Disorders, there were journals focused solely on multiple sclerosis and journals on neurology broadly, but not one that focused specifically on multiple sclerosis and the various and increasing number of demyelinating disorders of the central nervous system that are being recognized. So Multiple Sclerosis and Related Disorders was meant to be a home for sometimes comparisons, sometimes new insights, and certainly thoughtful reflection on the scope and breadth of demyelinating disorders in the central nervous system in adults and in children.

 

MSDF

Is there a certain amount of waiting, or it’s just the volume of papers that you get in that determines the mix between multiple sclerosis and other demyelinating disorders?

 

Dr. Banwell

Really it’s actually the quality of the papers we receive that drive the selection into the journal. To date, we have been blessed to receive some very interesting manuscripts, some of which relate to multiple sclerosis but many others relate to neuromyelitis optica, which is one of the disorders we were interested in; in antibody-associated encephalopathies; in patient perceptions of demyelinating disease, which is from the area that I think is very interesting and relevant; and then even some basic science, manuscripts that have looked at mechanisms of the immune system targeting the central nervous system.

 

MSDF

Is there a particular editorial philosophy?

 

Dr. Banwell

I guess the one my co-editors and I would say that we’re looking for manuscripts that push the envelope a little bit in terms of hypothesis generation. We like to see a thoughtful reflection on where the next step needs to be in the papers that we accept. And we’re not at all uncomfortable with being a little bit provocative in terms of perhaps people broaching new hypotheses as long as those hypotheses are well defended and can generate the next step of research.

 

MSDF

So it sounds like you’re also delving into basic science, or at least early clinical studies here, too?

 

Dr. Banwell

We’ll delve into it. We are not a basic science journal, so we would not pretend to be Cell or Nature or any of those sorts of journals. But certainly many of the manuscripts that we’ve accepted have discussed potential hypotheses based on basic science research and how that might tie to the clinical picture.

 

MSDF

One question that always arises with a new journal is why should people want to publish in this journal as opposed to some of the more established ones?

 

Dr. Banwell

Well, I think like any new journal, we have a lot of opportunity to accept manuscripts. We have very quickly gotten to the point where we have a very high caliber of manuscripts, which I think speaks to the interest in the field, so the journals that are arguably in competition with us are also now increasingly receiving high quality manuscripts as well. And I think overall it reminds us that there is actually quite a bit of research going on in multiple sclerosis and related disorders, and therefore there’s room for several journals in the field at this time.

 

MSDF

Is it now being indexed in PubMed?

 

Dr. Banwell

We have applied for indexing and we’ll hope to hear very shortly.

 

MSDF

Is there any problem or have you faced any barriers?

 

Dr. Banwell

No barriers. It’s just that you have to have a certain number of manuscripts published, you have to show that the manuscripts are of high quality, and you have to have been in the field long enough to actually have enough publications for them to judge the quality of what we’re doing.

 

MSDF

I see that you have co-editors-in-chief. Who are your colleagues in this?

 

Dr. Banwell

So there’s Dr. Chris Hawkes and Dr. Gavin Giovannoni from England, and Dr. Fred Lublin from the United States.

 

MSDF

Anything else important to add about the new journal or the things that it’s come out with lately?

 

Dr. Banwell

Well, we have a lay review author as well, and we do hope to increase some scholarly input from the lay public over time. Certainly we’re interested in maintaining the sort of price we put on novelty and in encouraging people to submit work that is perhaps looking at a new angle in the field. I think the related disorders aspect of our journal is an important component, both of the title and also of the concept. We are particularly interested in some of the emerging disorders that we now realize are potentially, if not multiple sclerosis, certainly in the field of immune-directed responses in the central nervous system. So I think that aspect of our journal speaks to an area of the field that might not have been previously quite so well captured in the existing journals.

 

MSDF

Does this journal lend itself to a more global approach to demyelinating diseases, since it’s multiple sclerosis and related disorders as opposed to just looking at MS as an isolated condition?

 

Dr. Banwell

Certainly in concept, yes. I think in fairness to the other journals that I think are all excellent and also in the field, we are not the only ones that are broadening the scope. And I think that speaks to the discoveries. So with the identification in 2004 of the aquaporin-4 antibody, and then subsequent to that really compelling evidence that the aquaporin-4 neuromyelitis optica story broadened and recognized a very specific subgroup of patients, that is also happening with other antibodies potentially, and there’s some emerging information about, for example, NMDA receptor encephalitis and other disorders that weren’t really recognized as such a few years ago. Our journal is prioritizing this type of sort of patient base and diagnostic categories, but so too are other journals that are also excellent in the field. So I think in fairness, everyone is recognizing that there’s more to the story.

 

MSDF

Is the NMDA antibody story with the catatonia?

 

Dr. Banwell

So NMDA receptor encephalitis is a disorder actually discovered by Josep Dalmau at Penn, so very near and dear to our heart here. The patients present sometimes with psychotic features, they can become quite catatonic. There’s been some lay publications on that. “Brain on Fire” was a book written by a survivor of NMDA receptor encephalitis. In children we certainly see – and in adults, but certainly in children – we see a number of patients present with severe seizures and then with abnormalities of movement. When these patients present they can be catastrophically ill, often in intensive care unit. Over time as the patients recover, miraculously it seems because it really does appear to be quite miraculous, the patients can have a full recovery. So it is a disorder that’s extremely important to recognize and can be misdiagnosed quite easily as an infectious encephalitis, as initially other psychiatric disorders, and in some patients as a really severe form of epilepsy, all of which it is, but it has a better overarching diagnosis. And making the diagnosis certainly gives hope in terms of long-term prognosis, and we do use specific therapies for the patients with the diagnosis.

 

MSDF

Very good, I appreciate it. Thanks.

 

Dr. Banwell

My pleasure.

 

[transition music]

 

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

 

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

 

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

 

 [outro music]

 

Jan 6, 2015

[intro music]

 

Host – Dan Keller

Hello, happy new year, and welcome to Episode Twenty-Six of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.

 

This week’s podcast features an interview with Tim Kennedy about remyelination and neural development. But to begin, here is a brief summary of some of the latest developments on the MS Discovery Forum at msdiscovery.org.

 

According to a new clinical trial, azathioprine, or AZA, may be as effective as interferon beta. The generic immunosuppressant was effective in both reducing relapses and reducing new brain lesions in the multicenter trial. This may not be surprising since the drug has been used off-label to treat MS for several decades. If trials continue to go well, AZA may become the go-to alternative for patients who can’t afford brand name interferons.

 

A pair of Canadian studies recently showed that both neurodegeneration and inflammation may start in the early stages of pediatric multiple sclerosis. One team found epitope spreading in the blood of children shortly after the onset of MS, suggesting a potential new diagnostic tool. Though children comprise only 2 to 10 percent of the MS population, data gleaned from them may provide insights into the disease as a whole.

 

If you enjoyed our end-of-the-year interview with Alan Alda and find MSDF to be helpful, please consider supporting us with a donation. We share Mr. Alda’s philosophy that closing the gaps between scientific disciplines is key to improving scientific progress. To make a donation, visit msdiscovery.org and click on the green “Support MSDF” button next to “Research Resources”.

 

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Now to the interview. Tim Kennedy is a researcher at the Montreal Neurological Institute. He met with MSDF to talk about the role of certain molecules and receptors necessary for oligodendrocyte development, maintenance, and function and their implications for remyelination.

 

Interviewer – Dan Keller

Welcome, Dr. Kennedy. Let's talk about the life of oligodendrocytes. These are important for myelination and probably play a role in remyelination. What is the life of an oligodendrocyte? How does it start out? And what does it react to?

 

Interviewee – Tim Kennedy

Many labs around the world have been studying the life history of an oligodendrocyte and also the lineage of the cells and how they differentiate during normal development. One of the reasons for doing this is that oligodendrocyte precursor cells are present in the mature nervous system and almost certainly contribute to remyelination in demyelinating diseases like MS. Oligodendrocyte precursors are born in the early embryonic CNS, and from the very restricted regions where they're born they then migrate away to populate all of the regions of the mature CNS where myelin occurs. In the lab here, we've been very interested in the molecular cues that direct and influence oligodendrocyte precursor migration. These include a family of proteins called netrins that we work on. And receptors for netrin like a protein called DCC. DCC stands for deleted in colorectal cancer. It was originally identified in cancer, and we now know that it has a critical role in the central nervous system in the migration, maturation, and maintenance of myelin by mature oligodendrocytes.

 

MSDF

Some of these molecules take on different functions as the oligodendrocytes mature. How do they react, or what do these molecules do over time?

 

Dr. Kennedy

When an oligodendrocyte precursor is born, it makes the netrin receptor DCC, but it doesn't make netrin. What the cell does is it responds to netrin in the environment, and through DCC reacts to it, and the netrin directs the cells to migrate. It tells them to initially migrate away from the position where they're born and sends them in the direction of axon tracks that require myelination. In mature myelinating oligodendrocytes, one of the huge surprises we had is that both of these proteins are made. Now, both netrin and DCC are required for normal neural development. If we examine a conventional knockout mouse that lacks either netrin-1 or DCC, those mice die within a few hours of being born, and there's a massive disorganization of the nervous system. So these are essential for normal neural development. When we look at the mature nervous system, we see that every single oligodendrocyte, every single mature myelination oligodendrocyte, makes readily detectable levels of netrin-1 and also the receptor for netrin-1, DCC. And a very simple statement of the question that we wanted to answer is what's the point of that? Why do these cells make these proteins that are essential for normal neural development but make them in the adult nervous system? In every adult human that we encounter, every single person, we're making netrin-1 and DCC in our brains right now. So what's the point? One of the functions that we've recently identified is that DCC produced by oligodendrocytes is required for the maintenance of myelin. Now what that means is that initially when we looked at the distribution of netrin-1 and DCC in relation to myelin we see that they're enriched at paranodal junctions. Paranodes are at the ends of internodes that are the regions of compact myelin that wrap and insulate an axon. The paranodes are a specialization that's made by the oligo that then connects it and ties it down to the surface of the axon. The paranodes flank the node of Ranvier, which is the key point, the specialized region along an axon that regenerates the action potential. So if we think of the internode of compact myelin as the region where the oligodendrocyte insulates the axon and allows the action potential to jump from node to node, the paranodes are the specializations at the end that tie it down. Now, the paranode is where we see the netrin and DCC enriched. If we take away either netrin-1 or DCC from oligodendrocytes, what we see is that the paranodes begin to come apart. Now in a very recent publication, what we did was use a genetic trick called cre-lox recombination to selectively take DCC out of mature myelinating oligodendrocytes. In these mice, the mice develop perfectly normally, the nervous system develops normally, the myelin develops normally. But then, at two months of age, we induce the deletion of DCC only from oligodendrocytes. Now having taken DCC out of oligodendrocytes, what we see is that first the paranodal junctions start to come apart, and then as we let the mice age the compact myelin itself starts to become disorganized. Now, that's interesting because what we're able to document in these mice is a progressive disorganization of the myelin produced by the oligodendrocyte. The progression is interesting, obviously, because we believe that this has identified a new mechanism that maintains myelin, and we would then relate that to the progression of demyelinating disorders like multiple sclerosis. A consequence of having lost DCC is that the action potential conduction velocity in the nervous system is delayed, and when we look at the mice themselves – and look at their behavior, put them through behavioral tests – what we see is that they become uncoordinated and slower in their movements. So again, this would all be consistent with this disruption of the myelin along the axons in the central nervous system due to the loss of DCC. And it's an indication that DCC being made by oligodendrocytes is absolutely essential to maintain the appropriate organization of myelin.

 

MSDF

That explains why myelin may become disorganized. Now, if there is a state in which it's already disorganized, which we look at someone with MS, is there any indication here how to remyelinate knowing what you now know about what's required for maintenance of myelin?

 

Dr. Kennedy

Certainly. What's really exciting having found that DCC is essential to maintain myelin is that this is a new biochemical mechanism that is required to organize and maintain the structural paranodal junctions, and that that's critical for the integrity and the maintenance of compact myelin. Now, DCC is a transmembrane receptor, and every single component of the signal transduction pathway downstream of DCC is potentially a drug target that could be manipulated to enhance the maintenance of myelin. So this is a new biochemical mechanism that exists in oligodendrocytes that promotes myelin maintenance. And that has enormous potential for trying to encourage the persistence of myelin in demyelinating disease.

 

MSDF

What about remyelination? I think you've said oligodendrocytes are born to myelinate. What's stopping them?

 

Dr. Kennedy

If we go back to the oligodendrocyte precursor in early development, what our studies of the developing nervous demonstrated was that oligodendrocyte precursors are repelled by netrin-1. The normal function of netrin-1 in the early embryo is to drive oligodendrocyte precursors away from where they're born so that they can go out into the rest of the central nervous system, find axons that need to be myelinated and myelinate them. That indicates that in the early embryo netrin-1 is a repellent for these cells. Again, we recently reported that in human MS plaques netrin-1 is present in those plaques. Where that's likely coming from is from the wreckage of cells that have died in those plaques. So I had said that mature myelinating oligodendrocytes express netrin-1. When those cells die and when the myelin is lost, the debris from those cells remains behind and potentially even builds up in plaques. There are a number of inhibitors of oligodendrocyte precursor migration that we now know are present in human MS plaques. These include proteins like chondroitin sulfate proteoglycans, semaphorins, and now netrin. What that strongly suggests is that when oligodendrocyte precursors are migrating in the adult brain to sites of demyelination with the intention of remyelinating an axon that has been demyelinated these inhibitors will very likely prevent those cells from entering the plaque and doing what they were born to do, which is to remyelinate. A very exciting thing about MS research today is that we know that the brain contains stem cells that produce oligodendrocyte precursor cells that readily give birth to these cells. So all of us have oligodendrocyte precursor cells in our head. Those cells are born to myelinate. They will migrate towards plaques where demyelination has happened, and if they're allowed to enter the plaque find the axon that needs to be remyelinated. And if they can be encouraged to overcome whatever it is that is blocking them from remyelinating, potentially that aspect of MS remyelination could be encouraged to happen.

 

MSDF

Do you have some ideas on how to overcome this blockage either clearing away the debris or making the oligodendrocytes insensitive to the inhibitors and the debris?

 

Dr. Kennedy
Both of those approaches would be very appropriate. So encouraging the nervous system to clear away the debris we would predict that that would encourage remyelination to happen. In addition, although I said there were multiple inhibitors present in MS plaques – and those inhibitors have different receptors – downstream of those receptors it's very likely that common signal transduction mechanisms are engaged. So targeting those common signal transduction mechanisms inside the migrating oligodendrocyte precursor cell could very potentially nullify all of the inhibitors at once. If it was possible to turn off the sensitivity to those inhibitors, then we would predict that the cells would enter the plaque more readily, and more of the cells would then be able to encounter the axons that require remyelination, and we would obviously predict that that would promote remyelination happening.

 

MSDF

What are some of the big questions now to look at, solve?

 

Dr. Kennedy

The oligodendrocyte is an absolutely fascinating cell type. It's a highly specialized cell type, critically clinically important. We still understand very little about these cells. The mechanisms that I've been talking about that regulate the maintenance of myelin, those have only very recently been discovered. And I think it's extremely exciting that this type of thing is being found in oligodendrocytes. But these are still very mysterious cell types. I think the more we understand about the cell biology of the oligo the more we'll be able to target pathways in the biochemistry of oligodendrocytes to try and promote things like myelin maintenance and the ability to remyelinate. Being able to do those things and essentially manipulate these cells in specific ways, we can then overcome specific clinical issues.

 

MSDF

Does this go beyond MS? Are there other conditions that it applies to?

 

Dr. Kennedy

I think there are two things built into that question. One is that there are many diseases for which the cause either isn't clear – and MS would be in that category – or there are also diseases that have many different causes, but they may manifest in similar ways. So by understanding oligodendrocytes and being able to encourage oligodendrocytes to remyelinate, that could have broad applicability for treating the symptoms of many different forms of demyelinating disease irrespective of the cause of those diseases. Beyond that, as we come to better understand how cells move in the nervous system, how they migrate, how they form attachments, how they connect to each other, and how they maintain those connections, those kinds of insights are going to have broad applicability for all sorts of neurodegenerative diseases where the basic problem in the neurodegenerative disease is that the networks that are the nervous system are coming apart. And if we can encourage those networks to just stay together or rebuild themselves, then I think that again has broad applicability to many types of neurodegenerative diseases in the myelinating field and outside of myelination, as well.

 

MSDF

It sounds like it may even have applicability to not only neurodegeneration but in development where you may have miswiring such as potentially an autism or something like that.

 

Dr. Kennedy

Yeah. An exciting thing is that a lot of the mechanisms that I'm thinking about and we're thinking about in the lab is that the insights that got us working on myelin, that brought us to work on myelin really came from neural development and better understanding neural development; the studies of neural development identified proteins and gene families that have very, very potent actions in the nervous system. When we then looked at expression, we saw that they were expressed in the mature CNS, and that brought forth a whole other group of questions related to the function of the normal adult nervous system and also the degeneration of the adult nervous system in neurodegenerative disease. The exciting thing about that is that as we understand the molecular biology of the central nervous system better that's going to be applicable to development, to normal function, to enhanced function, and also promoting function in degenerative conditions.

 

MSDF

I appreciate it. Thank you.

 

Dr. Kennedy

You're very welcome.

 

[transition music]

 

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

 

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

 

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

 

[outro music]

 

 

 

 

 

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