[intro music]
Host – Dan Keller
Hello, and welcome to Episode Thirty-Nine of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.
This week’s podcast features the second part of our interview with Joseph Berger of the University of Pennsylvania. But to begin, a couple of updates.
Last week we told you about our Drug-Development Pipeline, which includes continually updated information on 44 investigational agents for MS. Since last week’s podcast we added two new trials, we updated information on 10 other trials, and we added 10 other pieces of information. The drugs with important additions and changes are dimethyl fumarate, fingolimod, glatiramer acetate, interferon beta-1a, interferon beta-1b, and phenytoin. To find information on all 44 compounds, visit msdicovery.org and click first on Research Resources and then on Drug-Development Pipeline
Two weeks ago we described how we curate a weekly list of all newly published scientific papers on MS and related disorders. Last Friday’s list included 53 papers. We selected two of them as Editor’s Picks: One is a Cochrane meta-analysis of dimethyl fumarate – trade name Tecfidera – for treating MS. The other is a study from Paul Tesar’s group at Case Western Reserve University. That study, which appeared in Nature, is entitled “Drug-based modulation of endogenous stem cells promotes functional remyelination in vivo.” To find the full weekly list and the Editor’s Picks, click on the Papers tab at msdiscovery.org.
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Now to the interview. Dr. Joseph Berger is a professor of neurology at the Hospital of the University of Pennsylvania. In part one of his interview we talked about risk of progressive multifocal leukoencephalopathy. This week, Dr. Berger discusses diagnostic dilemmas in MS.
Interviewer – Dan Keller
Dr. Berger, how do these present, and what are some of them?
Interviewee – Joseph Berger
They’re legion, actually. There are a lot of different diseases that can look very much like multiple sclerosis both in terms of the history and physical examination as well as in terms of the radiographic findings. And the question is, do you want to avoid treatment that is not very helpful and expensive? You know, once you’ve made a diagnosis of multiple sclerosis you tend to put the patient on a disease-modifying therapy that they would remain on for the rest of their lives. And there’s an expense and some risk depending on what you put them on, associated with that. Secondly, there are diseases that, if you miss the diagnosis, these are diseases that can be aggressive in and of their own right, and if you’ve misdiagnosed it there’s a concern that disease may go on and create its own problems for the patient. So there are a variety of reasons why you want to ensure that what you’re dealing with is truly MS and not one of the MS mimics.
Among the common MS mimics, one that we’ve had increasing experience with in the recent past, is neuromyelitis optica. So, neuromyelitis optica was a disease that we lumped together with multiple sclerosis, but we’ve realized recently that not only is the pathogenesis different than multiple sclerosis, it being a humoral immune disorder, but that the therapies that we employ for multiple sclerosis may actually aggravate neuromyelitis optica. So that’s a common concern and one of the reasons why we frequently obtain neuromyelitis optica antibodies in patients, particularly when they present with optic neuritis or transverse myelitis, and certainly when they present with both of them.
MSDF
That would be aquaporin-4 antibodies?
Dr. Berger
That’s correct. It’s an aquaporin-4 antibody, but not everybody with neuromyelitis optica has the aquaporin-4 antibody that’s demonstrable. A certain percentage of them have what appears to be an anti-MAG antibody, and others we simply don’t know what the antigen is. And that’s being worked out. So there’s this whole spectrum of neuromyelitis optica that you certainly want to sort out from multiple sclerosis. But there are also a wide variety of other illnesses that can look like multiple sclerosis. In fact, if you take any broad classification of diseases – infection, vascular, neoplastic, toxic, metabolic, genetic, etc. – if you do that and say, are there diseases in these categories that can appear like multiple sclerosis and be mistaken for multiple sclerosis, there are. So every single one of these broad categories can have within it a disease that can be mistaken for multiple sclerosis.
MSDF
Would they be mistaken for multiple sclerosis on many measures or mainly signs and symptoms or is it radiologic on imaging? How do you sort out this kind of gamish of different diseases and how they present, and really nailing down an MS diagnosis, not even considering a diagnosis of what else it could be?
Dr. Berger
So it can be enormously difficult to do so. And I’ll give you some examples from my own practice. I have, for instance, seen individuals with a disorder called hereditary spastic paraparesis where you were unaware of their hereditary nature of their disease. And the patient has come in with a progressive myelopathy. And you say, well, could this be primary progressive multiple sclerosis? And could be extraordinarily difficult to sort out, particularly if they don’t have common mutations, and they don’t have a family history. And you say, well, which is it? The spinal fluid can be very helpful in that regard.
The MRIs can be very helpful in that regard, but not always. I’ve seen individuals who’ve had vascular disease where the MRI abnormalities have looked very much like multiple sclerosis. They’ve had recurrent episodes of neurologic symptoms be it numbness or weakness or visual problems, and it be mistake for MS. I’ve seen individuals with intravascular lymphoma, a rare disease, but one where they’ve presented with both clinical picture and MRI that looks very much like multiple sclerosis.
Although we have good diagnostic criteria, there is no single test that tells you that this is MS. But there are times when all of us, even the very best clinicians, scratch our heads when a patient’s reappeared in the office; nothing new has happened to him. Ten years have elapsed, and you say to yourself, did they really have multiple sclerosis? So, again, it’s a matter of comprehensive history and physical; the appropriate radiographic studies; looking at the spinal fluid when that’s indicated; and doing the appropriate laboratory studies to rule out things that may mimic multiple sclerosis.
MSDF
Is that why there is a diagnosis of CIS? If it never returns, then it was CIS?
Dr. Berger
I guess one could say that, but I use the term CIS to mean the very first episode of multiple sclerosis. So when I label somebody with CIS, I already believe that they have multiple sclerosis. I think that if they have CIS in the absence of any radiographic findings, I’d be unlikely to label them CIS. CIS to me is in the continuum of MS, so you have CIS, relapsing/remitting multiple sclerosis, secondary progressive multiple sclerosis. So that’s how I use the term.
MSDF
Can you definitely rule in or rule out multiple sclerosis?
Dr. Berger
I think that there are probably rare instances where people fulfill all the criteria for multiple sclerosis. And at the time of autopsy you say, how about that? That wasn’t multiple sclerosis. There’s an old expression in medicine that you can never be a 100% certain. You can never have a 100% certainty. So I think that you do the best you can. And I think that probably the rate’s 99% or better, but in these people fulfilling the criteria that have been established. However, you can never be entirely certain.
And it is not that uncommon in my practice, and I’ve been practicing medicine nearly 40 years, where an individual has presented the office after a long hiatus. And the chart is unavailable to me, and they come in with a diagnosis of multiple sclerosis, and I say, who made the diagnosis of multiple sclerosis in you? And they go, you did, Dr. Berger. So I think go down to the cave where they keep the charts that are over seven years old only to find out that they had all the criteria for multiple sclerosis; that they had oligoclonal bands, and they had hyperintense signal abnormalities on their MRI, and they had relapsing symptoms, but, you know, over the course of the last 10 years they’ve had little. And you scratch your head and say, geeze I wonder if this is truly MS?
There are probably people who carry this diagnosis, and there’s literature on it, that carry it incorrectly.
MSDF
Those criteria, even though it never turned out to be MS, satisfied a diagnosis of MS. When you see something like radiologically isolated syndrome, do you work it up for MS, or only once it presents later does it become MS?
Dr. Berger
This is a very difficult question, and we see this with some regularity, that is, the individual that has hit his head in a car accident or developed a headache that somebody’s decided to do an MRI on. And they come in with an MRI that looks all the world like a patient with multiple sclerosis, yet they have no symptoms and no signs on physical examination that is suggestive of multiple sclerosis. And the question then becomes, what do you do with them?
There’s currently a study in which that question is being addressed. However, I will tell you what I do, currently. I do look for multiple sclerosis. I look for lesions in their spinal cords because I think that if they have that, the prognosis can’t be good, and I would likely start somebody with lesions in their spinal cord, who I’m convinced has MS, on a disease-modifying drug.
I look their spinal fluid. And I look at their spinal fluid for oligoclonal bands, and, if I see that, I’m increasingly convinced that that’s what we’re dealing with. And I would be inclined to treat those people as well. Now whether I’m doing the right thing or not, I don’t know, but for others in whom there are no spinal cord lesions, there are no signs or symptoms, and the spinal fluid is pristine, I’ve elected to wait. That is not necessarily the consensus among the MS community. That’s simply how I practice, currently.
MSDF
People don’t need oligoclonal bands to have MS, though, do they?
Dr. Berger
No, not at all. So, we certainly see a fair number of people – and it depends on the study – who have pristine spinal fluids. That means no oligoclonal bands, no cells, no increased protein, no elevated myelin basic protein or IgGs who still have multiple sclerosis.
MSDF
What about fatigue as an initial symptom of multiple sclerosis? A lot of people have fatigue – tiredness. Is there a way to differentiate the fatigue of multiple sclerosis from just being tired or a sleep apnea or an insomnia or they just don’t feel good?
Dr. Berger
Well, I think your history is very helpful because the sleep deprivation and excessive daytime sleepiness is not the same as the fatigue that people with MS report. The fatigue that people with MS report is akin to the fatigue that one experiences when they have a viral illness. So when you have the flu you go, oh man, I just can’t get out of bed. I feel terrible. And that’s precisely what the people with multiple sclerosis have. And what’s so interesting is how common it is. So it’s been said to be the greatest cause of disability in the MS population. It’s an acceptable cause of disability; not blindness, not incoordination, not weakness, but fatigue.
And it’s curious, when I practiced in Kentucky, I had a number of patients who were wheelchair-bound, had very poor vision or had double vision because of paralysis ocular palsies, who went to work every single day. And then I had patients that looked as healthy as you and I, and they were on disability. And I said, well, why is it that you can’t work? They said, I’m just too fatigued. I can’t do anything. It’s affected everything.
So the fatigue is different, and getting back to the frequency of it, so in individuals who have been diagnosed with multiple sclerosis, and I was part of this study, if you look at large numbers of individuals diagnosed with MS or who are on disease-modifying drugs for MS and go back and look at their medical records prior to the time of the diagnosis, you will see that about a third of them had been labeled by their family physician or their internist as having one of two diagnoses: chronic fatigue syndrome or fatigue and malaise. They’re the only two diagnoses with fatigue in them that you could put into the ICD-9 classification.
So, this is striking that so many individuals have fatigue recognized, yet it’s an advance of their having any neurologic symptoms that were believed to be the consequence of multiple sclerosis. It’s not to say that they didn’t have them. You know, it might have been some transient numbness or transient tingling or slight weakness that went away that nobody ever thought was due to multiple sclerosis. So that we don’t know about. But what I can tell you is that prior to an established diagnosis of multiple sclerosis, roughly a third of individuals have been labeled by their family physicians with fatigue.
MSDF
It’s interesting that you make the analogy between this sort of fatigue and that with a viral illness like the flu. Could this be a prodrome telling there’s an inflammatory process going on? I mean, is there interferon release or are there other mediators that seem to be unique to this kind of fatigue?
Dr. Berger
I would like to think that that’s the case. I would like to think that this is due to the very same cytokines that cause the fatigue that’s associated with viral illness. That’s not been convincingly demonstrated, although it’s been proposed. I think it makes a lot of sense. Coming full circle, eventually, although most of my colleagues classify multiple sclerosis as an autoimmune disease, there must be a trigger for the autoimmune disease. And my own belief, coming to this from virological angles as opposed to coming at it from an immune angle, is that there’s probably some infectious origin.
One of the things that’s so striking is the association between Epstein-Barr virus and multiple sclerosis where virtually every adult patient with multiple sclerosis has evidence serologically of having been exposed to Epstein-Barr virus. Now I’m not saying that that’s necessarily the cause, but in some way it must contribute to the development of the disease perhaps in a way that low vitamin D levels contribute to the genesis of the disease.
MSDF
Is there anything you’d like to add about diagnostic dilemmas or any kind of a mental framework for approaching this sort of thing, in nutshell?
Dr. Berger
Yes. The one thing that I would say is never be too confident. Never be too confident. I found that my highest confidence levels were right before I took boards in neurology, which was a long time ago. And I thought I knew everything. And the more I practice neurology, the more humble I’ve become in terms of establishing diagnoses and selecting right therapies for patients. So I always have a healthy skepticism. I have a healthy skepticism of things that I feel certain about. And when patients represent to office I always question myself, particularly if there’s something that doesn’t fit with the diagnosis. And I think that that’s good advice to anybody practicing medicine.
MSDF
Very good! Thank you.
Dr. Berger
My pleasure.
[transition music]
Thank you for listening to Episode Thirty-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 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]
[intro music]
Hello, and welcome to Episode Thirty-Eight of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.
This week’s podcast features part one of a two-part interview with Joseph Berger of the University of Pennsylvania. But to begin, we’d like to tell you about MSDF’s Drug-Development Pipeline.
Twelve drugs are currently approved in the US for the treatment of MS, but there are many more drugs in various stages of clinical and pre-clinical development. We’re keeping daily track of 44 of them in our Drug Development Pipeline.
To visit the pipeline just go to msdiscovery.org and click on Research Resources, and then Drug-Development Pipeline. You’ll find a finely detailed, fully referenced, and easily searchable database of all 44 of those drugs. The database includes details on each drug candidate’s physiology, its progress through pre-clinical and clinical trials, and its regulatory and commercial status.
Science journalist Heather McDonald has managed this database since its inception, and she updates it continuously, whenever new information becomes available. In just the last week, for example, she added one new clinical trial to the database, she updated information on two other clinical trials, and she added 5 other pieces of information. The drugs with important additions and changes were dimethyl fumarate, fingolimod, glatiramer acetate, interferon beta-1a, interferon beta-1b, mitoxantrone, natalizumab, and RPC1063.
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Now to the interview. Dr. Joseph P Berger is a professor of neurology and Chief of the MS Division at the University of Pennsylvania in Philadelphia. In part one of our discussion with Dr. Berger, we’re talking about the risk of progressive multifocal leukoencephalopathy (PML), a rare but serious brain infection that occasionally arises in people being treated for multiple sclerosis.
Interviewer – Dan Keller
The topic of quantifying risk and mitigating risk comes up with certain immunosuppressive drugs, notably natalizumab in MS but also with other drugs as well in other conditions. What are some of the confounding factors? Why is this not an easy thing to approach?
Interviewee – Joseph Berger
Well, it’s not easy because it’s so unpredictable. Nobody would have thought that natalizumab would have uniquely predisposed to the development of progressive multifocal leukoencephalopathy. In fact, when natalizumab was introduced, if one would have attempted to predict what would have happened, you might have said, well, we’ll see a wide variety of opportunistic infections of the central nervous system, since this is a drug that prevents the neural immunosurveillance that is necessary to prevent these diseases from occurring. However, that’s not what we see. We don’t see the opportunistic infections of the central nervous system that we see in the AIDS patient; for instance, things like cryptococcal meningitis and toxoplasma and tuberculous meningitis, it simply doesn’t happen. What we see, on the other hand, is this unique increased risk for the development of progressive multifocal leukoencephalopathy. This was an entirely, in my mind, unpredictable event. I suspect that this is true of many of the other drugs that are now coming to market; that our experience with them is limited, they have what we think is a well-defined effect on the immune system – they’re not broadly immunosuppressant – yet our knowledge of the immune system is such that we don’t understand fully the downstream effects they have. And it’s only after we’ve used these drugs for a number of years do we have a comfort level with what sort of risks that are engendered by their use.
MSDF
But it’s not unique to natalizumab; other drugs can induce this whether in neurologic conditions or even rheumatologic conditions. Is that right?
Dr. Berger
Yes. In talking about PML, that is true that there are other drugs that carry black box warnings for the development of PML; however, there’s something unique about natalizumab and another drug that is somewhat related to it and now off the market called efalizumab, which was a drug which went by the name of Raptiva and was used for the treatment of psoriasis. So there are drugs that uniquely increase the risk of PML and there are those that marginally increase the risk of PML, and one shouldn’t conflate them. And though a drug carries a black box warning for PML, it doesn’t necessarily mean that the risk is the same as it is with another drug that may also carry such a warning.
And let me explain this a little further. If you look at natalizumab and you look at efalizumab, those are drugs that have been used for conditions that had never previously been associated with progressive multifocal leukoencephalopathy. So despite the fact… And natalizumab, as you know, is used in the treatment of MS and used in the treatment of inflammatory bowel disorders, in particular Crohn’s disease, efalizumab used in the treatment of psoriasis; these are autoimmune diseases. And prior to the availability of these compounds, we did some aggressive immunosuppressive therapies in the treatment of these diseases. We would treat them with drugs like Cytoxan and azathioprine and high-dose steroids; a wide variety of things were employed. Yet until the PML experience with natalizumab and efalizumab, we had never seen PML in the setting of multiple sclerosis, in the setting of inflammatory bowel disease, or in the setting of psoriasis. So that tells you that there’s something unique about the drugs that we’re using and that it’s not necessarily the underlying condition that is responsible.
The second is when you start the drug, you do not see PML develop immediately; it takes some time. So the experience with efalizumab was three or more years, the experience with natalizumab is typically 12 months; actually the vast majority of cases – over 80% - have been on natalizumab for 24 months, so they’re on the drug for a long time. The shortest latency from initiation to the development of PML has been a single case in which it developed within eight months; everything else is 12 or more months. So what is that telling you? That tells you that the drug is doing something fundamentally to overcome the barriers to the development of this disease and that it’s not simply opening up a gate and letting the horses out; it’s doing something to the pathobiology of the disease.
And then lastly, the incidence with which we see PML with natalizumab – and presumably with efalizumab, although the numbers were much smaller – is extraordinarily high in the appropriate context. So for natalizumab, the risk of developing PML, provided you’re on the drug for two years, you’ve seen prior immunosuppressive therapy, and you’re JC virus antibody-positive so that you have been exposed to the virus that causes this disease, if you have all three of those, your risk is on the order of 1 in 90 or thereabouts. That is a risk that is commensurate with what we see with HIV-associated PML, so it’s very, very high.
However, if one looks at these other drugs which I have called Class 2 agents in several papers now; drugs like rituximab, also a monoclonal antibody though directed against CD20, drugs like brentuximab vedotin or mycophenolate mofetil – which is CellCept – those drugs, too, carry black box warnings for the development of PML; however, the setting in which PML occurs with their use is almost always with a condition that already predisposes you to the development of PML. So with rituximab, for instance, it’s seen with lymphoproliferative disorders, or with transplantation, or with autoimmune diseases in which PML had already been described long before the use of rituximab for the condition. And the same is true with these other drugs.
The second is there’s no latency to the development of the disease, so this is strictly a stochastic event; you may start rituximab today and in two weeks’ time develop PML. There’s no way that somebody’s developed PML in two weeks’ time. What that indicates is that individual was predisposed to developing PML, that virus was already in their brain, it was percolating there, your immune system was suppressing it adequately so it wasn’t expressing itself. And now you’ve done something, you’ve tweaked it a bit and the PML is now expressing itself because you’ve introduced the drug, but the drug fundamentally is not changing the pathobiology of the disease.
Lastly, although we do not have good figures on this, but the best data that I have is that we’re talking about orders of magnitude lower risk with these other drugs. So rituximab, for instance, the risk is probably on the order of 1 in 30,000, or something to that effect. That compared to 1 in 90 when you have all the risk factors that I described with natalizumab. So we’re talking orders of magnitude difference. So I’d suggest that we avoid conflating these drugs when talking about PML risks, and I think that this is something that is generalizable for other risks; I mean, PML is just one risk, but we see other infections and other things that have occurred with other drugs that we’ve employed tweaking the immune system, and I don’t think that one should necessarily put all these drugs that cause these things in the same boat.
MSDF
These drugs that are used in other conditions that do in themselves predispose to PML, when they’re used in MS which as a disease does not, on its own, predispose to PML, these same drugs – azathioprine, cyclophosphamide, mycophenolate – add to the risk when you give natalizumab?
Dr. Berger
That’s what it looks like. So when Biogen looked at the data that they had available from the initial cases of natalizumab-associated PML, one of the risks that they identified was the increased risk of the development of PML in those individuals that had previously received immunosuppressive therapy. And it really didn’t seem to matter which immunosuppressive therapy it was, it was any immunosuppressive therapy. However, it may be different with the different immunotherapies, it’s simply that the numbers weren’t large enough for one to say that this was particularly associated with azathioprine. People in Europe like to use azathioprine often very early in the course of the disease, so they were seeing a bit more PML than we had seen in the United States at least initially. And it wouldn’t surprise me if there aren’t certain immunosuppressive agents that increase the risk significantly compared to others, but we simply don’t have that data. And what is known is that it really doesn’t matter, any of them can do that.
MSDF
Without really having a firm understanding of the pathogenesis of PML – you know the risks but maybe not exactly why it’s occurring – how do you come up with a framework for mitigating risk; is it purely empiric?
Dr. Berger
That’s an excellent question. So it turns out that this was a back-of-the-textbook disease; this was the disease that occurred very, very rarely. Between 1958 and 1984 in a review published by Ben Brooks and Deward Walker, there were only 230 cases that they were able to come up with; 1958, of course, is when the disease was first described. So this was a very, very rare disease until the AIDS pandemic where people developed some interest in it, and then it really became interesting when we saw it with natalizumab. And there’s been more resources put into the study of this disease since then, so that we do have a better understanding of the pathogenesis. But in identifying these risks, we’ve worked backwards; you know, we say, alright, what does natalizumab do? So why is it that we see this increased risk?
So in getting back to your question, we know that immunosurveilling the brain is important; so if you have a drug that prevents appropriate immunosurveillance of the central nervosus system, it should not surprise you that the risk of PML is increased. And we do think that the alpha-4 beta-1 integrin inhibition that occurs preventing the entry of JC virus-specific cytotoxic T lymphocytes into the brain is in a large measure – but not completely – contributing to the development of PML. We also know other things. For instance, the virus that we are likely infected with – and the infection occurs very early in our lives; seroepidemiologic studies indicate that most individuals that are infected are infected before the age of 20 – that that virus is a virus that is ubiquitous but incapable of growing effectively in glial tissues; it is a virus found in urine and found in the urinary tract, it’s found in kidney and renal pelvis and bladder, and it’s found in high concentrations in some people’s urine. That virus will not grow in the brain. So something has to happen to the virus.
Does natalizumab change that in some way? Well, we think it does. We think it does that by causing the release of immature B cells; these immature B cells can harbor JC virus, and that virus as these B cells mature there is an upregulation of transcriptional factors that transactivate the virus, it is occurring in a milieu that may uniquely predispose to a genetic rearrangement of the virus enabling it to become a form of the virus referred to as a prototype strain or a neurotropic strain that can grow in the brain. So we think that there are at least two very large barriers that prevent PML that are affected by natalizumab; there may be others. And as we investigate this disease further, our understanding may improve and these explanations I’m telling you will likely be expanded. And, in fact, it may be that some of the thoughts that we have are wrong, because the story with the B cells is actually somewhat hypothetical; there’s some preliminary evidence supportive of it, and that’s why I tell people that I’m fond of Ralph Waldo Emerson’s comment, that consistency is the hobgoblin of small minds. If I stand before you a year from today and tell you something different, it’s only because we’ve learned more about it.
MSDF
So how do you mitigate risk and how do you get the point across to patients to let them make informed decisions with you?
Dr. Berger
So this is difficult, but we lay the facts out to them. And the facts are that there is this risk of PML, the risk in individuals that are JC virus antibody-negative are very small, the product label puts the risk at less than 1 in a thousand; the belief is that it’s significantly less than that. The fact is that we do see individuals who are JC virus antibody-negative months before the development of PML – it’s rare but it occurs – and there have been studies, including my own, that have indicated that the antibody study doesn’t necessarily mean you’ve never been infected by the virus. So one shouldn’t conflate JC virus antibody negativity with never having been infected, but it is a very good marker for the development of PML, and it is one that needs to be monitored carefully at six month intervals.
So we lay out to the patients that if you’re antibody-negative your risk is infinitesimal and an acceptable risk, and that we monitor you carefully. The second is this is a disease that can be life-threatening, and if not life-threatening certainly severely debilitating – multiple sclerosis I’m talking about – and there are people that have very aggressive disease and will accept the risk of developing PML, knowing that the risk may be 1 in 100, but their risk of developing something that was going to leave them wheelchair-bound and totally disabled is very, very high, and they say I’d rather take the risk of the development of PML.
So we do know what the numbers are. There’s a table that’s been published and gets revised periodically that puts into it JC virus antibody positivity, duration of therapy broken up into 24-month epochs, and prior immunosuppressive use. So we know what the risks are; the highest are in individuals that are treated more than 24 months with the drug, are JC virus antibody-positive, and had previously received immunosuppressive therapies.
MSDF
What about monitoring for signs and symptoms of PML if someone does choose to go on some of these drugs?
Dr. Berger
Yes, so that’s very, very important. And we do have patients that even in the face of JC virus antibody positivity, we and the patient elect to continue them on the drug. And patients on natalizumab need to be monitored very carefully for the development of PML, and that is a combination of both clinical screening – there is a TOUCH program that queries for the development of symptoms that may be concordant with PML – unfortunately, you also see symptoms of that nature develop in MS patients, as well, so it’s sometimes difficult to tell whether it’s MS or PML – and at that point in time you definitely want to survey them with an MRI. And, in fact, many of us do MRIs at regular intervals in patients on Tysabri attempting to identify the disease – PML – when it is asymptomatic. And those people seem to do best; the prognosis both in terms of disability and in terms of survival is better when you pick the disease up while they’re still asymptomatic, and they have what one would refer to as radiographically isolated PML.
So it’s a combination of vigilance, asking the right questions, performing your physical examination, and obtaining period MRIs, and in those that are JC virus antibody-negative – or even the antibody-positive – repeating that study periodically. And the reason I say that repeating it periodically even in the positive patients is because what’s been demonstrated is that the higher your antibody titer, the greater the risk of developing PML. So there’s a threshold now that’s been identified and individuals above that range have a significantly higher risk of developing PML than individuals who are seropositive but below that level.
MSDF
And just to clarify; the TOUCH program is the Tysabri Outreach Unified Commitment to Health? This is what you’re referring to in terms of monitoring for signs and symptoms of PML?
Dr. Berger
That is correct. That is the risk mitigation strategy that is FDA-approved and that Biogen has implemented in an effort to decrease the likelihood of PML developing.
MSDF
Very good, thank you.
Dr. Berger
My pleasure.
[transition music]
Thank you for listening to Episode Thirty-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 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]
[intro music]
Host – Dan Keller
Hello, and welcome to Episode Thirty-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 Jeanne Loring, who works with human induced pluripotent stem cells in a mouse model of MS. But to begin, we’d like to tell you about one of the most useful features of the MS Discovery Forum.
Each week somewhere between 30 and 110 papers related to multiple sclerosis are published in the scientific literature. At MSDF, we endeavor to list them all, publishing links to a curated set of each week’s new papers every Friday at msdiscovery.org/papers.
The first step in curating this list is an automated PubMed query that pulls all papers containing the terms multiple sclerosis, myelin, optic neuritis, acute disseminated encephalomyelitis, neuromyelitis optica, transverse myelitis, experimental autoimmune encephalomyelitis, cuprizone, neurodegeneration, microglia, and several related terms. This query returns many false positives. MSDF editors read all the titles and most of the abstracts and make judgments about which papers are directly relevant to MS or related disorders. Last week, for example, the query returned 139 papers and, in our judgment, only 58 of them – 42% – were truly MS-related. Some weeks the proportion is even lower than that.
The query terms neurodegeneration, myelin, and microglia are responsible for most of the false positives. Neurodegeneration, in particular, returns many references related to other neurodegenerative disorders, such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, stroke, and hypoxia, to name a few. Editorial judgments on which articles are relevant are often subjective, and we frequently struggle with those decisions. It’s easy to decide relevance when an article actually mentions multiple sclerosis. It’s harder when it mentions only myelin or only Th17 cells. If you think we’ve missed an important MS-related article—or if you think we’ve included an irrelevant article—I hope you’ll let us know by emailing us at editor@msdiscovery.org. And we’re open to suggestions on how to adjust our PubMed query to decrease false positives and false negatives.
Once we’ve chosen which of the articles to include in the week’s list, we select between two and four of them as Editors’ Picks. Those are the week’s articles that seem to us to be the most important or interesting or intriguing. Once again, we invite readers to take issue with our choices. We’d love to hear about important articles that we have not designated Editors’ Picks or, on the contrary, Editors’ Picks that don’t deserve the honor.
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Now to the interview. Dr. Jeanne Loring is Professor of Developmental Neurobiology and Director of the Center for Regenerative Medicine at the Scripps Research Institute in San Diego. She and her collaborators have been testing human neural precursor cells derived from embryonic stem cells in a mouse model of MS. The cells are injected into the spinal cords of immunocompetent mice with a model of MS induced by a neurotropic hepatitis virus. The cells are rejected within a week, but in that time they suppress the immune system and induce remyelination.
Interviewer – Dan Keller
In terms of how you came upon your most recent finding about human pluripotent stem cells in the mouse model of MS, could you give me a little bit of the back story?
Interviewee – Jeanne Loring
Oh yeah, sure. It was really interesting. So Tom Lane and I set out to try to develop a stem cell therapy for MS using human cells. So as a control experiment, we took human pluripotent stem cells, in this case embryonic stem cells, and turned them into neural precursors; differentiated them just a little bit. And then we transplanted them into Tom’s mouse model of MS. These mice were not immunosuppressed, and so we expected the cells to be rejected. And this was just our first experiment. But the results were not what we expected. After the cells were rejected, the mice started getting better, and their clinical scores improved. And then after several months, these mice were almost indistinguishable from normal mice.
The first thing we thought was that we’d gotten the cages mixed up, and we were looking at something different. But we’ve repeated the experiment now more than a hundred times, and about 75% of the time we get the same result. So what this tells us is that these cells that we put into the animals are having some effect during the seven days that they exist in the animals that leads to both immunosuppression and remyelination and a clinical improvement which is quite remarkable.
MSDF
When you say 75% of the time, does that mean you get almost no effect 25 % of the time? Or does it mean that 75% or the mice? Because that would say whether you’re making your stem cells right or not.
Dr. Loring
It’s 75% of the mice.
MSDF
How do you explain it at this point, or where do you go from here to find a way to explain it?
Dr. Loring
So once we’d realized that we had a phenomenon that was repeatable, we realized that there was something special about these cells. And we tested other cell types, like the pluripotent stem cells that they were derived from, and human fibroblasts, and discovered that neither one of those was effective. And since then we’ve also tried other ways of making neural precursor cells, and those cells aren’t effective either. So it’s something extremely special about the cells that we used in these experiments, which is very lucky when you think about it.
So we’ve now, both Tom and I – even though we’re not in the same place – we’ve set out to try to find out what it is about these cells that gives them these properties. Our first sort of cut on this – our hypothesis – is that the cells are secreting something that has a lasting effect. Our sort of big picture idea is that there are probably more than one protein or glycoprotein being secreted. And together they suppress the immune system so they act on the inflammatory response so that they increase the number of regulatory T cells that are produced and decrease the other T cell types. And they induce remyelination.
So Tom is now working on trying to identify what factors these cells make that are inducing the T regulatory cells. And on my side, we’re trying to identify what it is that makes them remyelinate.
MSDF
When you make these cells, how do you know you got a good batch? Can you characterize them? Are there biomarkers, and you can say, “We did it right this time?”
Dr. Loring
Yes. In fact, that turns out to be really important because we did it wrong a few times. And we have a gene expression signature. It’s essentially diagnostic assay for this particular cell type. We’ve boiled it down to a set of qRT-PCR markers. And, because we have collaborators in Australia, we had to be able to transfer this quality control assay to them. So far it seems like those markers, I think it’s a group of 10 or 12 markers, seem to be predictive of the cells’ working in the animals.
MSDF
And just to clarify, that’s real time quantitative polymerase chain reaction? How are you going about characterizing what they’re doing? I mean, are you doing cytokine measurements or you’re looking at cells that get produced in the mice?
Dr. Loring
Tom is really handling the cells that get produced in the mouse. He’s doing the T cell analysis. What we’re doing, we developed an in vitro cell culture method to look for the effect of these cells on maturing oligodendroglia in culture. And we found that something secreted by these cells which shows up in their culture medium actually induces maturation of oligos – of OPCs – in vitro. I guess that’s another result that we didn’t expect to be quite so clear. So that shows that there’s something that is secreted by the cells. I mean, that’s the most likely idea. And on Tom’s side, he’s shown that the conditioned medium from the cells induces T-reg generation. And on our side, we’ve shown that conditioned medium from the cells induces oligo maturation.
So now we’re trying to figure out what it is in that conditioned medium because now we think we can do a cell-free therapy for MS if we can identify what the factors are. It would be much simpler for us to do even a protein therapy for MS than it is to do a cell therapy. So both sides are taking sort of a candidate gene approach in which we’re identifying the proteins that are most highly specifically expressed in the cells that work in the mice. We have a list of those proteins, and we’ve sort of snatched a few candidates out of that group, and we’re testing to see whether each one of those proteins in purified form has the same effect as the conditioned medium.
The other approach, which is more tedious but more likely to actually tell us what’s going on is for us to fractionate the medium into different sized proteins and then test each one of those fractions. We’re in the process of doing that right now.
MSDF
But it sounds like these cells are pluripotent. Not pluripotent in the normal sense of a stem cell leading to different lineages, but they have a couple of effects. One is the immunomodulatory, the other is regenerating oligodendrocytes. Do you think it really requires the gamish of proteins? If you fractionate them, will you possibly lose the signal? And that’s a big matrix to put back together again.
Dr. Loring
Yes, it is. And obviously, if we get no signal from our fractions, we’ll put our fractions back together again and try to find out whether – there are only three fractions, really, right now. So we’ll try different combinations of these fractions to try to find out if we can reproduce the effect. The effect is quite robust. We essentially get no maturation in medium conditioned by other cell types, but we get very strong maturation when we use conditioned medium from this particular neural precursor cell.
MSDF
If you only have three fractions now, is it because you just have chosen not to fractionate it even more until you know what’s going on?
Dr. Loring
Yes, we’re trying to hone in on it. So we don’t want too many different things to look at right away. I’m hoping that we find that only one of those fractions works, and that we can discover everything is within that fraction, but I really can’t predict what’s going to happen.
MSDF
It sounds like the approach would be to put everything in except one each time as opposed to keep adding back. You’ve got to find the one critical one missing that makes the thing not work.
Dr. Loring
Yes, and eventually we will do that with specific antibodies, but right now that is, since we don’t really have our candidates narrowed down enough, that isn’t a viable approach. But you’re absolutely right. We want to find out if that’s missing, whatever the things that are that are missing. And I’m hoping it’s not so complex that it’s five or six or seven proteins, because that’ll make it much harder for us.
MSDF
How do characterize the condition of the mice?
Dr. Loring
So that’s Tom’s area of expertise. It’s essentially an observation of the mice over time. We have a movie which I can show you, but I can’t actually do it in a recording. It’s quite obvious when the mice – they’re blind scored so the person who looks at the mice and sees how well they’re walking around doesn’t know whether they’re controls or experimentals. If you just see the movies that are selected at particular times after the cells have been transplanted, it’s quite dramatic. They have a much better clinical score. Essentially, they’re almost normal after six months.
MSDF
And how are you sure that the cells you injected into the spinal cord are gone, that they’ve been rejected completely?
Dr. Loring
That’s a good question. We used a method for live imaging of cells in which we use luciferase to label the cells. And then we used an instrument which allows us to image the cells in mice – in living mice – over time. So we did this in individual mice and saw that they disappeared over time. And after eight days we couldn’t detect them anymore. That doesn’t mean there isn’t one or two left because the resolution isn’t that high. We will go back eventually and look through sections of the spinal cords and see whether we can detect any. The other thing we can do is (skip 13:37) a human-specific markers. So we can just take a section of the spinal cord and find out if there’s any human cells in it at all, or any human genes in it at all. But we haven’t done that yet.
MSDF
Do the cells have to be gone? Have you tried injecting a second time?
Dr. Loring
No, we haven’t. We don’t know. We really don’t know. It would be very interesting if it reversed the effects. Then we’d really have a problem to solve.
MSDF
What else is there important to add or that we’ve missed that’s important to this kind of research?
Dr. Loring
So our dream is that we will identify a group of proteins and the concentration of those proteins necessary to have these two effects in this mouse model. And then we will do some biological engineering. We’ll be putting the cells into these little spheres and matrix that allows slow release of these proteins or controlled release of these proteins. And then, instead of putting cells in, we’ll put these beads in. And I don’t know whether that would end up being the final product or not, but there are lots of ways to deliver proteins, and this one I find rather attractive because it doesn’t require pumps or syringes. And I think that’s certainly the direction we’re going to try to go in. And so Tom Lane and I have just gotten an NIH grant for five years of funding, which seems like a very long time to me. So in five years we will have discovered the best way to deliver these things. We’ll discover what they are and the best way to deliver them. Tom has put conditioned medium into the mice, and it also works.
MSDF
Because I was going to ask, had you encapsulated the cells just to see that the supernatant does it without cell contact?
Dr. Loring
It turns out that the conditioned medium itself, you inject that into spinal cord, it’s not as dramatic an effect, but you have a clear clinical improvement.
MSDF
Have you tried injecting it either IV or intraperitoneally?
Dr. Loring
Yes. Well, we didn’t inject the conditioned medium. We did try injecting the cells, and they pretty much stayed where we injected them. These cells, unlike mesenchymal stem cells, they aren’t very migratory. So they don’t really have the receptors that cause them to move to areas of inflammation like CXCR4, for example; they don’t express that on their surfaces. So that does not seem to be a good delivery method for these cells. They don’t go anywhere.
MSDF
I was also thinking that if something they secrete is important, whether it circulates. Maybe they’re not making enough concentration if you inject them outside of the central nervous system, but it seems like you’re going to be faced with a little cumbersome problem in a clinical situation years and years ahead from now if you have to keep injecting proteins into the spinal cord as opposed to more peripheral.
Dr. Loring
I agree. And the solution to that is generally to look for peripheral effects and then try to suppress those when you do a therapy like this. That’s a long time, and we could certainly imagine how we would do it. But we need to know what those proteins are before we can decide on whether we expect them to have effects peripherally or not. But I agree with you; delivering them intravenously would be far easier.
MSDF
I know you have a lot of work ahead of you now with this, but is there another animal model of MS – or even another mouse model of MS – where you can see if it works even in a mouse model different from this one?
Dr. Loring
Yes, we’re actively pursuing that with our collaborators in Australia. And it’s interesting because they’ve gotten some positive preliminary results using the EAE model, but the approach to the EAE model I’ve realized is quite different. Generally, what people do is they provide the therapy at the time that the pathology is developing, and they try to prevent it, which is a really different idea than what we had using the mice that are already paralyzed. So they have found that if you can deliver the cells at least close to the spinal cord, then you can see some effects. The problem is that in Australia, and this is one of those technical things we had not anticipated, they don’t have permission to inject cells into the spinal cord. So they have to go through their animal rights people or their animal protection groups and try to get permission to do so. So with Craig Walsh at UC Irvine we have started doing parallel experiments with the EAE model. I’m not necessarily sure that it’s going to have similar effects. I mean, I really don’t know.
MSDF
Can you describe how these mice in your experiments were made to have MS?
Dr. Loring
Yes, they were given a virus, a neurotropic virus, which kills off the oligodendroglia. They become demyelinated, and there is a secondary inflammatory response. So the mice are actually paralyzed in their hind quarters at least by the time we put the cells in. They have to be fed by hand. So this is not a trivial thing to do. But we’re trying to reproduce the effects during the progressive form of MS, for example, or during an attack of MS. So we’re trying to repair the mice or cure the mice that are in a condition which would be similar to the worst case scenario for people with MS.
MSDF
Do you think this may also have effects not only on the myelin, but also on damaged neurons?
Dr. Loring
We don’t know, because the mice haven’t really had enough time to get a lot of neuronal damage, but that’s a very good question. We don’t know yet.
MSDF
I appreciate it. Thank you.
Dr. Loring
You’re welcome. It was a pleasure.
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Thank you for listening to Episode Thirty-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.
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Dan Keller: Hello, and welcome to Episode Thirty-six of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.
This week’s podcast features an extended interview with Jenny Ting, an immunologist who studies the inflammasome, a multi-protein oligomer that’s part of the innate immune system. But to begin, we’d like to tell you something about why we started the MS Discovery Forum.
MSDF, located at www.msdiscovery.org, is an online portal providing news and information about research in MS. We offer a unique combination of news and background articles written by professional science journalists, viewpoints from thought leaders and subject matter experts, and technical resources that enable sharing and analysis of information and open discussion among MS stakeholders in academia, industry, and the clinic. Membership in MSDF is free, and all content on the site is provided on an open-access basis to the entire MS community.
MSDF stands apart for its comprehensive and independent coverage of MS research. Readers can depend on MSDF to report and verify, not merely re-run press releases. MSDF’s overarching goal is to accelerate progress toward clinically useful advances.
We launched MSDF in April 2012 with the aim of filling a knowledge gap in MS research. The plan was to promote collaboration among scientists who are separated by specialized skill sets, institutional boundaries, and geography. It’s well known that these individuals attend different meetings and read different journals. And while it’s common knowledge that scientific breakthroughs and medical advances most typically result from cross fertilization of ideas, in today’s world scientists still do not easily share ideas and collaborate on solutions. We wanted to change that, and to bring thoughts, knowledge and ideas out from the lab into the open to enlighten and inform all stakeholders in the effort to cure MS, including health care providers and people affected by MS.
To that end, we employ the highest standards for independent journalistic reporting, including the use of multiple viewpoints to give a full picture of a finding’s impact. We aim to make scientific findings accessible to everyone, from busy clinicians to cutting-edge researchers to people with MS and their loved ones. We avoid short-cuts, such as the use of jargon, that get in the way of comprehensibility. We highlight the potential clinical impact of the research we cover, even when we’re covering basic research that may be years from direct clinical relevance. And we seek innovative ways to communicate important information to our audience.
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Now to the interview. Dr. Jenny Ting is Professor of Microbiology in the Institute for Global Health & Infectious Diseases at the University of North Carolina at Chapel Hill School of Medicine. In addition to MS, Dr. Ting’s research interests include the role of the immune system in infection, inflammation, and cancer. Science Journalist Carol Morton caught up with Dr. Ting at a recent Keystone meeting.
Carol Morton: I appreciate your taking time out to talk to MS Discovery Forum. So we’re at the Keystone meeting on Neuroinflammation in Taos, New Mexico, and you gave a very interesting talk today.
Jenny Ting: Thank you.
Morton: So can you tell us what you’re talking about when you’re talking about the inflammasome and the particular proteins that you’ve been looking at.
Ting: The groups of proteins that we work on are cytokines, and cytokines are made by immune cells. And they have a tremendous impact on inflammatory responses. As you know, in MS there is a big immune component, so these cytokines will influence it. And in most cases cytokines activate the immune system. One of the key cytokines that we’ve studied is called IL-1, interleukin-1 beta; this is the one, for example, that causes fever, inflammation, and so forth. So it’s called interleukin-1 because it was the first one discovered, and it turns out it’s probably one of the most important ones.
So because it’s a master cytokine, and once it goes it kicks off all the other cytokines, so there’s a cascade that goes on. So it could activate other cells to make other cytokines, so it’s like a vicious cycle. Obviously, this becomes a pretty important target to think about. The process that causes this cytokine to be produced is a very big molecule that’s comprised of different proteins. And these different proteins, they are, together, called the inflammasome for inflammation large complex because “some” means large complex. Inflam- is inflammation, as in inflammasome. It’s the name given by Jürg Tschopp.
And so this process where you have this big complex, and as a result you get the cytokine called interleukin-1 beta, what happens is that interleukin-1 beta has now been implicated in so many diseases including arthritis, very rare diseases that causes a lot of inflammatory responses. It’s involved in skin allergies. It’s involved in colitis, you name it, and it’s involved in smoke-induced chronic obstructive pulmonary disease, COPD, that we see advertised on TV. So all of these have this component of this molecule.
Morton: So anything that releases IL-1 beta, inside the cell there’s a cluster of proteins that have to come together to make it.
Ting: Right.
Morton: And then it gets secreted and does its job.
Ting: Yes. And as we learned today, and actually it’s been published, but may be new to some of the audience, is that this whole complex can also be excreted in some ways into the cell, you know, pushed outside of cells so it can go from perhaps one cell to the other. So we have previously found that this can be a complex that’s membrane bound, and that’s called an exosome. So it’s both just like a minicell that goes from one cell to the next and make the next cell inflammatory as well. The speaker today showed that, in addition to that, it can also go out as a complex, perhaps naked. It seems like they are not really membrane bound, so that’s a different form. So it could be different forms that goes out from one cell to the next causing inflammasomal activation in the next cell and therefore perpetuates this IL-1 process.
Obviously, in normal hosts there must be a way to turn off this process, otherwise we would be, you know, a little ball of pus sitting on a chair. So obviously these don’t go on forever. The problem with chronic inflammatory diseases is many of these things, they don’t go on probably all the time, but they do increase. So what we did is really look at mice lacking genes that can make these proteins. This complex is usually comprised of at least three components; you knock out one and you can’t make IL-1 anymore. Actually, I should say five components. So we did that, and what we found was that if you take this out, the models of MS suggests the well-known mouse model, EAE, and another model that we’ve been really pushing, although it was initially worked on in the late 1960s and early 70s, this model of neurotoxicant-induced demyelination. In both of those models this process of inflammasome/IL-1 turned out to be bad.
So if you remove this process, the disease is much more attenuated. So that’s one of the really interesting parts about what we had found is that potentially this could be a target. And the good thing is that there is certainly some companies that have successfully made anti-IL-1s. So there is an IL-1 receptor antagonist that inhibits this process. There is an antibody against IL-1 that will inhibit this process. So certainly there are therapies, if this is true, that this is part of the MS problem that this could be used as a therapy.
The other thing we have found, which I didn’t get a chance to talk about, is that we did look at the remyelination phase and found out that, for example, IL-18 is not very good for remyelination. Of course, remyelination is what everybody would like to have, is a reparative process. And so one possibility is, can we block the IL-18 pathway, and can we get better remyelination processes. So those are some of the thoughts that we have.
Morton: So have you examined a number of the ILs from 1 to 18 or…?
Ting: No, because 18 is the product. So this inflammasome actually has many different targets. One of them is IL-1 beta; that’s the key one. Another one is IL-18. So we went from there to look at what’s downstream of the inflammasome and found out that IL-18 actually has a role both in making MS disease models worse and in reducing the extent of remyelination. So it doesn’t look like it’s a great protein to have around. So the question is can we try to inhibit this molecule.
Morton: Just to make sure that I’m clear on that: the inflammasome is a cluster of proteins that come together in an immune cell, like a T-cell, or a…
Ting: Usually it’s a macrophage or a microglia or an astroglia.
Morton: A macrophage or a microglia. And then that makes the IL…
Ting: So what you have is – I don’t know if the audience might be familiar with the coagulation pathway where you have one protein that has to be cleaved into a smaller protein. Then this protein B goes and cleaves a second protein from a bigger form to a smaller form. And the smaller form, in every case, is the mature protein that has activity. The bigger protein is the inactive form that doesn’t do anything. So this exactly the same. Pro-IL-1 has to be cleaved into IL-1. Pro-IL-18 has to be cleaved into IL-18. And what that cleavage process is this inflammasome complex producing an enzyme that will cleave these proteins.
Morton: So the inflammasome is like Edward Scissorhands running around cutting proteins making them active.
Ting: Yes, that’s a great analysis. So it’s just exactly like that. The inflammasome produces this – like you said – Edward Scissorhand that then this guy can go and prune the roses and prune the bushes, and they’re different, and they have different functions.
Morton: And it’s the starting block for the activity of the IL-1 and IL-18.
Ting: Right, so the bushes are like – if the roses are the IL-1, you can decorate it; you can give it to somebody; you can make it into a bouquet. So that’s the kind of idea. And then if you have a bush, you know, you can potentially do other things with it. Or if he’s cutting some edible plants you can use that for cooking. So that’s the whole idea. Whatever you produce has different effects. And it turns out IL-18, in our hands, looked like it’s not a good molecule. We have previously found that a cytokine called TNF, which has different roles depending on what it binds. So if it binds to TNF receptor 1, then it’s not so good. If it binds to TNF receptor 2, it actually enhances remyelination, so again, something you want.
And there’s recent talks and there are small molecules where people tried to activate the TNF receptor 2 pathway, and they found that that really enhances the remyelination process. It’s kind of really neat; if you can dissect these pathways well enough, then you might be able to use drugs to target MS.
Morton: So what are the next questions that you’re asking? Where are you going from here?
Ting: So we have a number of directions. Certainly, like I say, I raised the concept of IL-18; so can we target that molecule? In our own lab we’re also looking at several other pathways. So we have found a pathway that’s really important for cell-cell interaction that’s important for MS activation. And the molecules are called plexins and semaphorins. And this is a pair of proteins that seems to activate the immune system especially during MS. So we’ve done that in disease models, and we actually produce a blocker of that pathway. And we have treated mice, and they look much better. We showed that when they’re going through relapse, we can actually prevent them from coming back with a relapse.
So, very similar to some other MS drugs that are on the market, we’d like to think about this as additional possibilities. So those are some of the things that we’re doing.
Morton: What cells are these on?
Ting: These are T-cells and dendritic cells so they’re…
Morton: They’re talking to each other.
Ting: Yes, exactly, they’re talking to each other. And in an MS situation they talk to each other, they activate T-cells, which destroys the myelin. So if you can block that interaction, many of the drugs that are used for MS actually are targeting exactly that interaction pathway. For example, Tysabri is one that’s not so much dendritic cells and T-cells, but it reduces T-cell migration through the vasculature into the blood brain barrier. So that’s one of them where they block T-cell activation. So we are trying to block T-cell activation as well, but at the face of these two cell types.
Morton: If the inflammasomes, if they were superheroes or characters in an Oscar-winning movie, what would their personalities be, do you think?
Ting: I think they would be very powerful because they impact a lot of disease processes, yet they have very strong roles so that, when they’re used properly, they can defend against all sorts of stuff. Whey they’re used improperly, they can really cause a lot harm. So if they’re a superhero, people always say Batman has a dark side, right, a really dark side and a really good side. Maybe that’s what they are.
Morton: That’s a good analogy.
Ting: They’re not like Superman because Superman seems like all good.
[transition music]
Keller: Thank you for listening to Episode Thirty-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 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.
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