B (14:26)

Myelin is the fatty substance that protects the nerves in your brain and spinal cord, and Ms. Is called a demyelinating disease because in ms, the immune system mistakenly attacks the body's own myelin. While myelin repair is a natural function, it eventually stops working for people with Ms. New research may explain why and point to new possibilities for future treatments. Joining me today is Dr. Larry Sherman.

A (14:56)

Dr. Sherman is a professor at the

B (14:58)

Oregon National Primate Research center at Oregon Health and Science University, and his research focuses on how the brain and spinal cord respond to injury and disease, particularly in conditions that involve demyelination, like multiple sclerosis. Welcome back to the podcast, Dr. Sherman.

C (15:17)

Thanks, John. It's great to see you.

B (15:19)

I like to begin these conversations by getting our definitions in order, so I hope you'll start us off by explaining what myelin is and the role it plays in Ms. Sure.

C (15:30)

So myelin is a substance that actually wraps around nerve cells, and it has a lot of different functions, one of which is to protect those cells, the nerve cells. But probably the more important function, especially relevant to MS, is that myelin increases the speed at which nerve impulses travel through those nerve cells. So I always like to talk to people. I lived in Germany for a while, and the autobahn in Germany has no speed limit. I always like to tell people that if you have myelin, it's like driving on the autobahn at midnight, where you can be going 200 miles an hour and no one's going to stop you. And if you don't have myelin, it's like driving on the busiest highway in the United States at rush hour, where you're lucky to be going two miles an hour. And that's about the actual change in speed. Myelin is so important because if you think about what our brain is, it's a computer, and it has to be a very fast computer. So all these different parts of the brain have to talk to each other, also talk to our spinal cord and reach out to the rest of our body. So having myelin is critical for that. And if you lose myelin, all of that goes away. So in ms, your immune system, for reasons we still don't entirely understand, decides that myelin is foreign and attacks it and strips it off of the nerve cells. And now you're going two miles an hour instead of 200 miles an hour.

B (16:51)

So once we're stuck in that gridlock going two miles an hour, what types of symptoms might someone develop as their myelin becomes damaged?

C (17:01)

Yeah, so just about every symptom we see in people with Ms. Is a result of losing that myelin. So it's very important for your motor functions, your ability to move. It's very important for sensory functions, your ability to feel things and sense things, and also can cause pain, for example, because of misfiring. And then finally, it's really important for cognitive functions. Our ability to learn and remember things can be impacted by losing myelin. So just everything our brain does can be impacted by myelin loss.

B (17:33)

You know, as I mentioned when I introduced this segment, myelin repair is a natural process, but over time, that process stops working for people with Ms. Do we know why?

C (17:45)

We have some hints, and my own research suggests that at least one of the factors is a change in things that are happening outside the cells that make myelin over time. And so you're right. In early stages of ms, we think there's a lot of remyelination happening. The cells that make the myelin come back and they make more myelin, and everything's usually okay. There's a second process that happens, and that is that it turns out throughout our lives. This is kind of relatively recent data. We have these cells in our brains that are called progenitor cells. And these cells, when there's injury to myelin, kind of move over to where the injury is, and then they turn into the new myelin forming cells. They're called oligodendrocytes. And so these cells make myelin, and these other cells make myelin forming cells. And so over time, what we're finding is that we get this kind of pile up of these progenitor cells that should be making new myelin forming cells, but they're not. They're stuck. And so we've been trying to understand some of the signals that prevent that from happening.

B (18:54)

Your research has highlighted that the brain often tries to repair itself, but gets stuck. Can you tell us more about that?

C (19:03)

Yeah. So in our research, one of the things that we figured out that's preventing remyelination is a molecule, or an enzyme, I should say, called cmip. CMIP stands for cell migration and Hyaluronic Acid binding protein, which is a lot harder to say than cmip. So CMIP is an enzyme and what it does is it chews up a molecule that you've probably all heard of called hyaluronic acid. It turns out that hyaluronic acid isn't just for facial creams, which is where most people hear about it. Hyaluronic acid gets made whenever there's damage in any part of our body, including the brain. After these assaults on our myelin by our immune systems in ms, hyaluronic acid piles up and it's probably good at first, it's probably limiting the inflammation, but over time, when there's lots of Ms. Attacks, it starts to pile up to excess. There's too much of it. CMIP comes along, it's being made by these cells that turn into the myelin forming cells and starts chewing that up to degrade it and get rid of it. But if there's too much harnic acid, the little pieces of harnic acid that are made by that enzyme form feedback on those cells and tell them not to become myelin forming cells. And so if we could attack this enzyme, that might be a strategy for myelin repair.

A (20:23)

I was about to ask, how might

B (20:25)

targeting CMIP influence future treatment for someone living with ms?

C (20:30)

Yeah. So we've been spending the last several years trying to develop a drug that stops this enzyme from doing its job. And we've now come up with several drugs that are good experimentally. And what we found is that if we stop CMIP activity during demyelination, it actually promotes and accelerates remyelination. And we actually start to see some of the neurons, they're not back on the autobond exactly, but they're going about 75 miles an hour. And that's pretty good. And so, and we see some functional recovery as a result of that. So right now we're trying to find better drugs that really limit this effects of this broken down pieces of hyaluronic acid by preventing them from being created in the first place.

B (21:17)

If we can successfully remove those biological breaks that prevent remyelination, what might that look like for A patient. Do you see? And I think you've already started to answer it, whether it's a reversal of their symptoms or maybe just a stabilization

A (21:32)

of where they are.

C (21:33)

So we've actually tested that question in both mice and also in a non human primate model of Ms. In mice, we see really good functional recovery. The problem with any strategies that are really trying to repair the brain in mouse studies is a mouse brain is only that big. It's really tiny. It's really physiologically very different than our brains. My lab is out at the Oregon National Primate Research center, as you mentioned. The reason I came here was because back in the 80s, we had a group of Japanese snow monkeys that spontaneously developed disease that looks very similar to multiple sclerosis in humans. In fact, we think it may even be caused by the same things that cause Ms. In humans. We've taken the drug now to these animals that have demyelination in their brains and spinal cords. So far, the drugs, we have been able to show remyelination in those brains as well. But we're getting them at a stage of disease that's pretty far along. And the drugs are not optimal yet. They're not quite perfect as drugs. We can see remyelination happening, but now we got to go to the next step and see if we can get it to actually promote recovery, bring back motor function, bring back the sensory problems, and actually improve cognitive function as well.

B (22:52)

You just said something that I find fascinating. You said this. These Japanese snow monkeys spontaneously developed Ms. So this was not something that was induced in a lab.

A (23:04)

This. And.

B (23:05)

And so the work you're doing actually has the potential to cure them.

C (23:11)

That's what we're hoping. My whole reason for coming to the center was to cure these monkeys, because I figure if we can cure these monkeys, whose brains are much more like ours than the mouse brains, we'd have a really good chance of having something we could take to humans. The other thing these monkeys may tell us, though, is how Ms. Starts, which I think would be incredibly exciting. We think it's triggered. We have great data showing that it's triggered by a combination of a genetic liability that's similar to genes that we know are affected in Ms. Patients and a virus that arose in that colony back in the 1980s. And the virus is very similar to a virus that's been linked to Ms. Epstein Barr virus. So we think that on the one hand, they're great for trying to figure out how to fix the brain. On the other hand, they may tell us how to stop Ms. In its tracks.

B (23:58)

You've spent years at OHSU moving concepts from the lab toward clinical application. What's the biggest hurdle in getting a promising myelin repair molecule through human clinical trials?

C (24:11)

We've seen a lot of labs that have come up with different strategies to promote remyelination, and that work is ongoing, just beautiful work from lots of different people. And I think we're all sort of converging on similar ideas in terms of what pathways and cells we want to go after, including from hyaluronic acid and cmip. The challenge is to get, again, I think, going from these model systems into the human brain. And that's one of the things that I'm really excited about, having this monkey model, because having the monkey in the middle really gives you an opportunity to see if this will work or not before taking it to the clinical trials. The trials that we've seen so far have been not exciting, really. I mean, there's some excitement around some of the things that people have been able to see, but they're not quite where we want them to be yet. And so I think having better platforms for testing this before we take it to people is going to be a really important thing to overcome.

B (25:08)

It's occurred to me that while we're talking about the mechanics of myelin repair, I'm wondering how brain atrophy impacts the ability to induce myelin repair.

C (25:21)

So that is a challenge, right? Because the problem is, if the axons, which are the little threads that myelin wraps around on the nerve cells, if they're gone, then there's nothing to remyelinate. And as we lose nerve cells, we're going to lose the ability to promote remyelination, obviously. So I think for progressive stages of disease, the really important thing is going to be combining strategies for remyelination with strategies for neuroprotection. What I mean by neuroprotection is saving the nerve cells themselves, the neurons. There's a lot of people studying that right now. There's some really promising work coming out of multiple labs looking at neuroprotection. If you have now something that's going to promote neuroprotection and then something else that's going to remyelinate those axons that are protected, then you start to have real possibilities for the more progressive stages of disease.

B (26:14)

You and I actually last spoke nearly eight years ago in episode number 67 of this podcast.

A (26:21)

So if we were to sit down

B (26:22)

again in another eight years, what's one breakthrough in myelin repair you're most confident

A (26:29)

that we'd be discussing.

C (26:31)

I think in eight years I don't have a crystal ball and so this is completely speculation. I think in eight years we're going to understand so much more about the molecular basis for how myelin works and how myelin is made and then how myelin comes back, that we're going to have so many better strategies for myelin repair than we have now. The thing that I think we now know is it's possible. And if you'd have asked me that 20 years ago, I would have said I don't know because we just didn't have the data to suggest that was true. Now we know it is possible. All the experimental data from all these models that we've been testing show you can promote remyelin repair. Now the question is we need to get all this data together and find exactly the right way to do that. And I think in eight years we're going to have a much better sense idea of what the right strategy will be.

B (27:28)

Dr. Larry Sherman, I want to thank you for all you and your Japanese snow monkeys do to effectively improve the lives of people living with Ms. Thanks so much for talking with me today.

C (27:39)

Thank you, John. Great to see you.

A (27:41)

That's going to wrap up this episode of Real Talk. Ms. Real Talk, Mississippi is powered by the National Ms. Society and you can share this episode of the podcast by letting your friends or family members know that all they have to do is is point their web browser@realtalkms.com 452. You'll find that link in today's show Notes so you can easily copy and paste it right into an email or a text. Next week on Real Talk. Ms. My guest, Dr. Riley Bovet, tackles one of the most important and personal topics for many women living with Ms. The intersection of Ms. And and the journey to parenthood. Navigating family planning with a chronic condition can sometimes feel overwhelming, but Dr. Bovet brings world class expertise and a reassuring perspective to the conversation. We'll be discussing preconception planning and how to manage disease modifying therapies. When you're ready to start a family, we'll look at why women with Ms. Often see a reduction in relapse activity during pregnancy and will review practical strategies for managing the increased risk of relapses after delivery. Whether you're currently planning a family or looking to support someone who is, I hope you're planning to join me for next week's episode of Real Talk. Ms. I'm John Strum. Thanks for listening. Stay safe and make healthy choices.

C (29:16)

Sam.