Matt Hoffman, Senior Editor for NeurologyLive, has covered medical news for MJH Life Sciences, NeurologyLive’s parent company, since 2017. He hosts the NeurologyLive Mind Moments podcast, as well as Second Opinion on Medical World News. Follow him on Twitter @byMattHoffman or email him at firstname.lastname@example.org
The medical director of the UCSF Multiple Sclerosis Center provided some insight into the development of therapies for the purpose of remyelination.
Ari Green, MD, MCR
For many physicians, the next big goal in the treatment of multiple sclerosis (MS) is remyelination—repairing the damage to the central nervous system done by the disease.
Ari Green, MD, MCR, medical director, UCSF Multiple Sclerosis Center, and director, UCSF Neurodiagnostics Center, is one of those physicians. He not only has a belief that these therapies could work, but has also worked closely on many of them. Based on that experience, his opinion is that some may work better than others.
Much of this ability to develop these therapies have come from the knowledge gained over the last 20 years about the disease course of MS. While the field still lacks an understanding of when the disease specifically begins to affect the body, it is closer than it has ever been.
To delve into Green’s expertise with these therapies and the understanding of the progression of MS, NeurologyLive® sat with him at the 34th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) annual meeting in Berlin, Germany.
Ari Green, MD, MCR: I'm a bit biased here for sure because this is actually what my research focuses on and my laboratory focuses on, and I've worked closely in collaboration with another scientist, Jonah Chan, PhD, who's a myelin biologist. We work to identify pathways that would be attractive and molecules that would be attractive, and then work to validate them and, in fact, did the first successful human clinical trial in patients with a chronic lesion, trying to see if we could remyelinate in that setting. So, just as a full disclosure, I have an absolute and unquestionable bias in that regard. A secondary bias that I think it'd be important for clinicians understand is that because I've worked in that space, I've provided some counseling and advice to companies that are specifically targeting that approach and I have particular opinions about approaches that will work.
My strong opinion is that a small molecule approach is much more likely to be successful than an antibody-mediated approach. Some people have postulated the use of antibodies because of their specificity—which is an advantage of antibody approaches over small molecules. But their negative is the target is in the central nervous system, and antibodies are huge and don't get into the central nervous system via the blood-brain barrier very easily. They would have to be given and, in fact, in clinical trials have been given, in extraordinarily high doses in order to be able to get enough of them into the central nervous system to, hopefully, have some biological effect. That's not an optimal setting. Antibodies work well as immunomodulatory agents because the target is largely in the periphery, is largely in circulation. Trying to get those drugs into the central nervous system is a challenge, so small molecules, I think, is really the way to go.
The thing with small molecules is that you have to know what your target receptors are, so you can develop drugs that are selective for that target receptor as much as possible. That's another important area that I think is where the exciting area of biology is going on. People have suggestive data about particular pathways—I think a few of them are attractive, I happen to think a few are somewhat more attractive than others, that again revolves around my own biases about things that I've been working on and investigating. But working on what are the actual targets that might be capable of encouraging OPCs to turn into oligodendrocytes—that that molecular exploration is ongoing and has led to the identification of whole new pathways and biology. The understanding is going to come when we ultimately are able to draw those things together, and I think that will be really important for the development of the therapeutics, which is starting but is in its earliest stages.
The epidemiology research that even extends back into the middle part of the 20th century has taught us a tremendous amount about what the potential factors are that are associated with disease development, and by identification of those factors, give us a strong indication about the probable timing of exposure. I think we have a pretty good sense that, at least for the majority of patients, there's probably some exposure in adolescence, maybe late childhood, or potentially, in some people, early adulthood, that sets them up. That gives us an indication that the disease probably begins to operate at some point in that stage, up to the point of when disease really starts to manifest, which is on average at the beginning of the fourth decade—the average age worldwide is about 30 to 31 years old. If you think about that, there's probably a period somewhere between a few years, up to maybe 10 or 15 years, over which the disease percolates. I think we have indications both about what are the potential environmental factors that are contributing to disease development and then what is the timing of when that starts to kick off. The challenge is that we don't have a way to screen everybody on that front.
But a hugely important point, I think especially, for everyone to understand—even outside of MS—is that why do we have therapeutics in MS? In part, it's because although we can't identify the earliest stage which it develops, we identify it way earlier than we do with other degenerative diseases like Parkinson and Alzheimer. Parkinson and Alzheimer may also be diseases in which the very start of it is in early adulthood, or maybe at the latest, in middle adulthood, and yet, we have no real understanding of when those diseases are starting and who's at risk and what's happening. In MS, because the early clinical features of the disease are syndromic, they're clinically manifest, so people have attacks—those attacks are not the degenerative component of the disease. The attacks, though, identify who has the disease and allow us to start intervention at an early enough stage that we can have an effect. If you look at areas like Alzheimer, the only lesson I'm drawing from those areas, not being an expert, is the only way those drugs are going to work is if they're started early enough. Most of the problem we face is not that we don't understand the biology—we don't enough, there's more to be done, but we have developed some understanding—it’s that we just can't figure out who are the earliest patients that are showing the first signs, and how could we try drugs in the early enough stage where they might have a chance of success.
I think the same thing exists for the other neurodegenerative diseases, just to differing degrees. MS is unique. The first manifestations occur early enough that we can both start interventions and people are young enough that the youthful brain is probably a little more resilient and a little more capable of recovery from damage or injury.
Transcript edited for clarity.