Multiple Sclerosis Discovery -- Episode 6 with Dr. Jeffrey Dunn

[intro music]   Host – Dan Keller Hello, and welcome to Episode 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 Dr. Jeffrey Dunn, who explores the prospect of personalized medicine in MS. But to begin, here’s a brief summary of some of the topics we’ve been covering on the MS Discovery Forum at msdiscovery.org.   Recently, blogger Emily Willingham shared a person experience with MRI interpretation in our blog, MS Patient, Ph.D. She wrote, “I’ve come to realize in my various dealings with MRI reports that neuroradiologists are like economists; everyone has an opinion and no two readers will agree on what they see in exactly the same data.” Willingham, a developmental biologist, provides a unique view into the life of an MS patient. Her experiences bring a first-person perspective of MS, while her scientific background informs her insights in a way that many researchers and clinicians may find valuable.   We’d also like to bring your attention to the data visualization section of the MSDF website. Under the research resources tab, you can find a series of interactive data visualizations useful for MS researchers. One visualization aggregates 106 clinical trials. You can organize the data by the compound, phase, population, or even the funding. Our latest visualization is of the natural history of MS symptoms. The interactive bar chart allows you to see the change of various symptom severity in MS over a 30-year period.   Also in research resources, check out the drug development pipeline. This is where we keep detailed information on, at last count, 40 drugs currently in development or on the market for MS. This database, which is updated daily as new information becomes available, contains a wealth of data on each agent. This includes the agent’s class, its intended target and routes of administration, its regulatory status and commercial history, its chemical properties, mechanism of action and adverse effects, and all its clinical trials.   Now for the interview. Dr. Jeffrey Dunn is a Professor of Neurology and Neurological Sciences at Stanford University. He met with MSDF editor Bob Finn to discuss the use of biomarkers and personalized medicine. But first he shared a little history.   Interviewee – Jeffrey Dunn So, in the history of multiple sclerosis, when cases of CNS demyelinating disease were first discovered, they were discovered as isolated case instances at a number of different and variable institutions throughout Europe and in the United States. The doctors knew of the patients’ symptoms, of course, because they had cared for them. Many of these patients went on to pathology examination, and multiple cases of areas of inflammation or even scar formation were seen within the central nervous system. These cases from the mid-1800s and into the late-1800s were described as isolated instances. And the physician who is given credit for the discovery of what we now know to be multiple sclerosis was Dr. John-Martin Charcot in Paris, because he had had the experience of a very close relationship with a patient he named Mademoiselle V. He had known that she had had a tremor and ataxia and eye movement abnormalities, so Charcot knew his patient’s phenotype, her clinical manifestations, very well, and specifically had seen evidence of eye movement abnormalities, tremor, and ataxia. She had consented to have her nervous system evaluated pathologically, and so Charcot was able to make a connection between what she had looked like in life, and then what her brain and spinal cord had looked like after she had passed away.   It’s that clinicopathologic correlation that really was a paradigm-buster at the time. And Charcot found palpably hard spots – areas of gliosis or scar formation – that occurred in plaques and patches throughout the spinal cord and brain (and cerebellum in this case). He called the disease almost an adjective really; he called it “la sclérose en plaques”, which is French for sclerosis – meaning hard spots essentially – in plaques. So hard spots was the disease. Multiple sclerosis is really an adjective more than a diagnosis. But in the early 20th Century leading up to the mid-20th century, there was increasing recognition on the basis of these isolated case reports that this disease that was now increasingly being called multiple sclerosis might be far more common than people had realized, and great credit needs to be given to Sylvia Lawry, who as you know was the founder of the National Multiple Sclerosis Society. The National MS Society was put together to try to bring physicians together to create a forum by which they could crosstalk, share the anecdotal information each of them had compiled, and come up with a more systematic review so that the disease could be better described and so that treatments could be more likely discovered. This was a huge step forward in terms of our discovery and ability to diagnosis and ultimately later to treat MS, but it created a framework that said that MS was, in some respects, one disease.   Now all of us even today, I would say, as physicians are trained that MS is a distinct disease; that it’s one type of disease with many variations according to individuals, but I think we’re actually at the very beginning of a very important paradigm shift in this consideration. There’s a difference, of course, between a disease and a syndrome. A disease is a quantifiable isolated entity – a classic example might be a genetic disorder caused by a single mutation in a coding sequence of DNA – whereas a syndrome is probably a collection of different but closely related diseases. I think there’s increasing evidence now, an increasing recognition that MS may be very heterogeneous and variable across individuals; I don’t think there would be any argument among my colleagues that MS is a heterogeneous process. My suggestion to you is that now, I think, we’re at the threshold of a paradigm that says that MS should not be regarded as a monolith or a single pathologic entity, but maybe more as a Stonehenge; a collection of closely related conditions that share some common pathology, but that need to be considered on an individual basis.   At the clinical, radiologic, immunologic, and pathologic levels we have evidence that MS is very heterogeneous among individuals. I think the theory that we now need to proceed according to is that multiple sclerosis is not one disease entity, but a number of different conditions. This idea and paradigm of personalized medicine is gaining traction. Our oncology colleagues who treat cancer have used this with some great and promising success in terms of applying optimum regimens and chemotherapeutic protocols to their patients, but I think there’s tremendous opportunity in multiple sclerosis to practice personalized medicine, because I think that the process of MS is a personalized one in which there are unique and eminently measurable proteins or protein profiles one day we’ll be able to identify, and hopefully that day is soon, and we can use that as the rationale for our prescription for the patients.   Interviewer – Bob Finn So when some people think about biomarkers, they think about an individual protein or some other biological signal that will be prognostic or in some other way tell you about what the patient is experiencing or might experience. It sounds to me like you’re talking about not an individual biomarker, but a constellation of biomarkers that would provide a fingerprint. Am I right about that?   Dr. Dunn I think so. Just as the disease pathogenesis itself is heterogeneous, I don’t think that one single protein would be able to help us. What I would foresee as an individual approaches us, that we might do a panel. There’s a series of questions that has to be asked. The immune process itself is sequential and acts, I think, as a cascade, and we have some biomarkers today that are available. I think you could argue them as biomarkers that help us in decision-making, that help the clinician decide what might be the best therapy, at least in terms of risk-benefit balance, but we just don’t have enough of them to be able to make the kinds of personalized decisions that I think we all hope we’ll be able to make one day.   MSDF Would you mention a couple of the ones that are – or some of the ones – that are available now?   Dr. Dunn So one example that I think would be well agreed on is the presence or absence of JC virus infection that can now be measured by a two-step ELISA assay, with a false-positive rate of an estimated 2.5%. One of the great challenges we face in treating MS is that we have to, in some respects, down-regulate the immune system to protect the brain and central nervous system, but we can’t overshoot the mark to cause a systemic immunosuppression. Immunosuppression can manifest in a number of different ways, including opportunistic infections and even malignancy. One of the most lethal and daunting of the opportunistic infections is a condition called progressive multifocal leukoencephalopathy – that’s precisely why we tend to call that PML instead, three syllables is far preferable – and that condition is caused by an infection of an otherwise relatively benign virus called JC virus, that if it gets into the central nervous system and begins to affect oligodendrocytes and cells of the central nervous system, can cause rapid intracellular proliferation and damage to the brain; that can spread geometrically throughout the brain and can cause very profound brain damage, and sometimes cases of death as well.   We’ve known of PML previously in patients with lymphoma and also in patients with untreated HIV infection who had severe and advancing immunosuppression. But we’ve seen this same PML condition in immunocompetent patients who have been treated with some of the agents that we might use for multiple sclerosis. This concern is not unique to MS, but it’s a concern with any immunotherapy that you use. The ability to measure whether a patient has previously been infected with a JC virus or not helps us in the risk-benefit balance considerations we have to make on behalf of our patients. It’s known that the absence of evidence of a JC virus infection is associated with a markedly decreased risk of PML, whereas its presence means that’s an active consideration in our prescribing.    Now that, I think, functions as a biomarker. Any time you might see an elevation of a measurable protein or another biomarker in general that normalizes with remission that gives you the opportunity to suggest that that either might be a therapeutic target – so let’s just call it protein X, for example, just for simplification and clarification. If a patient having an MS attack has a measurable increase in protein X in their blood which then now returns to normal or what had been their previous baseline in remission, that tells the clinician investigator that protein X might either be part of the immunologic cascade that causes the MS attack, and therefore suggests that the ability to intervene, down-regulate, or modify the expression of protein X may help with disease pathogenesis, OR it could also mean, or it could emerge as a candidate as a tool of assessment for disease status, so that one question we always have to ask as clinicians when we start patient on any given therapy or just in following them is how are they doing. Of course, that’s a primary mandate for the clinician taking care of patients.   Today, we do that by asking how they’re feeling, we strive to get into quality of life metrics with them, we also turn to their examination findings to look for interval change, and we look at MRI to see if there’s been a change there, with the hope that we’re seeing no evidence of disease activity. But the field of multiple sclerosis does not have its own version of a hemoglobin A1c, such as our endocrinologists have. In that scenario for those that aren’t familiar with it, A1c can be a value obtained literally with a single drop of blood that tells the practicing clinician caring for the patient what the average blood sugar of that patient has been over a substantial period of time prior to the time of their clinical encounter. So it helps the clinician make wise judgments and counsel to the patient regarding the optimum way to treat their diabetes, whether adjustments have to be made in their diet or in their prescription medications.   We don’t have such a thing in multiple sclerosis today. If we could find such a thing, it would make our care, I think, far superior in its quality. I think it would make physicians’ advice to our patients far more wise, and it would make the entire medical enterprise of caring for the MS patient less expensive, because we wouldn’t have to resort to important but still somewhat stodgy and expensive technologies like serial MRIs done with what could be high-frequency for the patient. Serial MRIs are safe for the patient, but you can see that if we could identify such a biomarker as that, if that were possible, I think that would have revolutionary implications for our care of the MS patient, not just in reducing medical costs – that’s an important goal – but the more important goal and what physicians need to focus on is superior advice, improved advice and counsel to the patients that are in our care.     MSDF So you and I are both old enough to remember when the Human Genome Project was proposed, and one of the values of the Human Genome Project that was articulated was that it would usher in an era of personalized medicine. Now it’s 13 years or so after the Human Genome Project has been completed, and, arguably, that promise has never been realized. How much longer will it take in multiple sclerosis to realize an era of personalized medicine?   Dr. Dunn The short answer is I don’t know, but there’s some important considerations to be made along the way. One fact is there are approximately 25,000 genes in the human body, but there are an estimated 500,000 proteins. The reason for the difference is that after an original protein is manufactured on the basis of the blueprint of DNA, it can be modified in transcription and translation. For those of you in your field, this would be post-production modifications. The same thing happens with proteins, and what that means is that the field of proteomics, you could argue, is 20 times more sensitive than the field of genomics if the ratio is 25,000 to 500,000 genes to proteins in the human body, respectively.   MS does have a genetic component, and that’s been proven by research in this past two decades by our country’s leading researchers, but the genetic input of MS is not the only answer; MS is only partially a genetic disease. It seems to be, in my own opinion and I think it’s shared by my colleagues – many of them, most of them perhaps – is that MS is primarily an environmental condition. The greatest risk of obtaining MS is not so much that family members are affected, though cases of that have happened and happen regularly, it seems to be more related to environment, where one lives. Now you may know that epidemiologically, MS is almost absent, or very sparse, at the equator, but in moving north and south on Earth, the greater that one moves away from the equator, the greater the prevalence of MS. And right about the 35th parallel or so both north and south of the equator, there appears to be a relatively large increase in how much MS there is. And that’s true, to the best of our knowledge, all the way around the world.   And so if MS is more of an environmental condition than a genetic one – although it’s both – then I think a genetic assay may be part, but not likely to be all of the answer, and the promise of going to a more sensitive assay to get into the post-transcription and post-translational modification that takes place in human molecules, which ultimately are the language of how the immune system affects our nervous system, is going to be and prove to be a more enriched and more promising field of inquiry.   MSDF I wonder if you can mention some of the labs that are doing the most promising work in this area.   Dr. Dunn I’m pleased to say that there are labs throughout the world that I think are doing research in this. Within the United States – I don’t want to leave anybody out – but I think that special kudos need to be given to the Mayo Clinic. I think on the east coast the Partners Program of the Harvard Medical Schools are very interested in this field; Johns Hopkins is doing work that I think is exemplary. Out west, our colleagues at UCSF. And, of course, I have to give special kudos to my colleagues at Stanford University. These are places that are publishing in translational medicine the bench-to-bedside framework in which discoveries that are being made at the level of the bench, there’s an active effort being made to try to translate that to human care. I’m very sensitive to the idea of excluding anybody, because I think that this is really an international search, and it’s going to require multilevel of collaboration. So I hope that as we go forward, we’ll be able to really work together.   I mentioned just a moment ago, I think practice of personalized medicine in this field is going to require not one discovery, it’s going to require a panel, perhaps, of different measurable biomarkers. I don’t anticipate one single lab is going to be able to discover all of those biomarkers, I think we’ll get one discovery from one place, one from another, one from another. And it’s going to require a transcendent collaboration between institutions and individuals and researchers and investigators to bring it all together for the collective good.   MSDF Dr. Dunn, thank you very much.   Dr. Dunn Okay, alright, thank you very much, Bob.   [transition music]   Thank you for listening to Episode 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 nonprofit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is Vice President of Scientific Operations.   Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.   We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to [email protected].   [outro music]