A (3:19)

Yeah. When myelin stripped off of these axons, the nerves, then that puts them at risk for degenerating over time. And maybe part of why we see progression of disability in people with Ms.

B (3:30)

Absolutely. And this is why there's such a big push to discover drugs for Ms. That can support remyelination, because after the demyelination, we have a time window in which we could really come in with a drug, support remyelination before that nerve would start to degenerate.

A (3:49)

So you mentioned these cells, the oligodendrocytes, wrap themselves around in the central nervous system, which is your brain spinal cord. What about in the periphery of our bodies? So in the nerves that go down to our arms and legs, how is the myelin different there?

B (4:03)

For the most part, the myelin is pretty similar in the central nervous system as it is in the peripheral nervous system, but there are some differences. So, for example, one difference is in exactly what the myelin is made of. The composition is almost the same, but there are some slight differences in the proteins. And the other big difference is that the myelin is made by different cells. So in the central nervous system, we've talked about the oligodendrocytes that put out many arms to make myelin on many different nerve fibers. In the peripheral nervous system, myelin is made by cells called Schwann cells, and Schwann cells actually only make myelin for one nerve fiber.

A (4:46)

Unfortunately, there's a few people out there that have demyelination in their central and peripheral nervous system, but most people, it's two separate conditions. What about the optic nerves? So the nerves that go from the eyeball to the brain, the optic nerves.

B (5:00)

Are often one of the first places that are affected by demyelination in Ms. So sometimes one of the first symptoms of Ms. Is actually an issue with vision. What's also interesting about the optic nerves being myelinated is that this is now being used as a way to monitor remyelination in clinical trials. And so one way to measure whether you have more myelin that's now been produced through remyelination in a clinical trial is to test how quickly a visual signal would travel from your eye into the brain. And actually, it's been quite a useful tool to be able to understand and test whether drugs are influencing remyelination.

A (5:44)

Yeah, that's important. And I think it's also kind of interesting because those oligodendrocytes are the ones that create the myelin. So as opposed to the Schwann cells.

B (5:52)

Correct. Yeah.

A (5:53)

So let's dive on into what exactly is demyelination?

B (5:58)

So demyelination means that we have loss of myelin due to damage. We're still discovering exactly what causes demyelination in ms, but one contributor is thought to be immune cells that are confused and think that the myelin is something that they need to attack, like an infectious agent or something like that. And so demyelination causes symptoms in Ms. Because with the loss of the myelin now, the nerves don't function properly. We've talked about the importance of myelin in that it provides insulation for those electrical signals. If you lose that myelin now, those signals cannot travel quickly enough across the nerve fiber in order for the nerve to do its job. We've also talked about how myelin is important in providing the energy requirements for the nerve and survival factors for the nerve. So if the myelin is missing again, the nerve is not healthy. It's not getting what it needs to do a good job. And if the demyelination lasts long enough, the nerve fiber can actually die. In the absence of these survival signals that myelin would normally provide.

A (7:12)

Is it possible for people, after having an Ms. Attack, to remyelinate? Is it naturally something that happens?

B (7:20)

Yes. So this is quite exciting, actually, that we. Remyelination can occur naturally. The remyelination process is more efficient in early phases of Ms. During the relapse, remitting phase, but also in younger individuals.

A (7:36)

When you think about people with ms, an attack can come on very rapidly within a few days, but then it can take weeks or sometimes months to heal. Why does it take so long for that to happen?

B (7:49)

So the recovery from relapses isn't just about repairing that myelin. There are a lot of other things that are going on during that process as well, like resolving inflammation. For example, we know from MRI imaging remyelination can take weeks to months to occur. But we don't know why this is. And one thing we do know is that oligodendrocytes need to make a lot of myelin, and this takes a lot of energy. So as mentioned, they put out a lot of arms. They're making myelin for a lot of different nerve fibers. This requires a lot from the oligodendrons site and even from experiments in a dish in experimental models, we know that this can take weeks. So in ms, it might be slowed down Even further by cells and molecules that are in the lesion. And in the field, we're still discovering what these cells and these molecules are.

A (8:45)

Yeah. So I think when the immune system comes in and starts attacking, all these cells come in, immune cells, lymphocytes. And the damage happens very rap. I think people don't realize that those oligos have to wrap themselves around and around and around to create the myelin. It's. It's not just instantaneous. Kind of think of it like an octopus. The cell body is like the main part of the octopus, and then all these arms reaching out, tentacles and just wrapping around. And that takes time for that to happen, as you mentioned.

B (9:16)

Yeah, that's a great analogy with the octopus. And it does take quite a lot of time. But there are also a lot of different steps in the remyelination process that need to occur before the oligodendrocytes can even make that myelin. And that slows down the process even further.

A (9:30)

So you're a scientist, so let's go down to the cellular level. Can you introduce us to the oligodendrocyte precursor cells, or what we call the OPCs, and what role do they play in repairing damaged myelin?

B (9:44)

So oligodendrocytes are the cells that make myelin, and these are mature cells. This means that they are fully capable of carrying out their function. They actually are made from oligodendrocyte precursor cells, which is abbreviated opcs. These opcs are stem cell like cells that mature into oligodendrocytes. I like to think of it as akin to a child maturing into an adult. And OPCs are really important for remyelination because remyelination requires new oligodendrocytes to be made so that these new oligodendrocytes can regenerate the myelin and make new myelin.

A (10:28)

Yeah. So these OPCs are common in normal people. Right. 5 to 8% of the cells in our central nervous system consist of these OPCs. So we do have the capability, the hardware, so to speak.

B (10:40)

That's absolutely right. So Everybody has these OPCs in their central nervous system. We have a lot more of them when we are younger, before we've generated a whole bunch of our oligodendrocytes. But even as adults, like you said, about 5% of our total cells in the central nervous system are OPCs. And there's really interesting research in the field figuring out if these OPCs have roles other than just sitting there waiting to see if they have to participate in remyelination. They might have Some other important roles in the central nervous system as. But it's quite useful for us that if we do have demyelination, that these cells are kind of on standby.

A (11:18)

What prevents full remyelination? So if someone has an Ms. Attack, let's say, in their spinal cord, and they get numbness and weakness in the legs and they get better, but they still have numbness in their legs, is there things that are preventing full remyelination in people with ms?

B (11:32)

So one important roadblock that limits remyelination in Ms. Is age. This is because of changes that occur in the OPCs, but also in other supportive cells that are involved in influencing the remyelination process. This leads to these cells having less capacity to carry out their positive functions in remyelination. Another important roadblock that limits remyelination is that OPCs are less able to mature into oligodendrocytes with Ms. Progression. So this is a really important finding that has really spurred the testing of drugs for remyelination in clinical trials for Ms. For the first time that are aimed at boosting OPC maturation into oligodendrocytes. And the third thing that can limit remyelination is really blocks on how well the new oligodendrocytes are able to make new myelin. We don't yet have any drugs aimed at boosting the actual production of myelin once an OPC has become an oligodendrocyte. But our lab has recently published a study, which we're really excited about, that showed that immune cells from the blood called monocytes reduce the ability of oligodendrocytes to make myelin once they have been newly generated during the remyelination process. And so now we're currently working towards finding ways to use this information to move that towards a therapy in future.

A (13:10)

Yeah, so let's dive into that a little further. So you mentioned monocytes as being one of the factors that can affect remyelination and demyelination. And specifically, there's a cell microglia that's a type of monocyte that has significant interest in the world of Ms. We see these microgl glia around the rim of chronic lesions in the brain. So how does microglia play a role in remyelination? I think you're a global expert on this topic.

B (13:37)

As you've mentioned, microglia are actually an immune cell that live in the brain and spinal cord of all of us permanently. They actually are a type of macrophage. So this is an immune cell that it literally means big eater. And monocytes can also turn into macrophages. And so what this means is that once there is myelin damage and there is this debris that has been generated from the demyelination, one way in which microglia can help remyelination is by clearing out that debris. It's like taking out the garbage. And that's really important because if that debris is not cleared up, it actually blocks the OPCs from coming into the lesion, and it also prevents the OPCs from maturing into oligodendrocytes. So that's one positive role of microglia in remyelination. Another thing that they do that supports remyelination is secreting factors that act on the OPCs to encourage them to become oligodendrocytes.

A (14:45)

What are those factors?

B (14:46)

Well, we're still discovering what they are. One factor that our lab discovered is involved is called active in a. But there are a number of different molecules that are known to be released from microglia. These are called growth factors, and they can act on proteins on the surface of OPCs. It causes signals within the OPCs that instructs the OPC to then mature and become an oligodendrocyte.

A (15:10)

So microglia can be positive for remyelination. Can they also be detrimental?

B (15:15)

On the other hand, the ability of microglia to support or hinder remyelination depends on their state. So, for example, we as people can be in a happy state or an angry state. In the same way, microglia can have different states. So they can be in a state that supports remyelination, but this can change into a damaging state, and this occurs with age. For example, they can change into a state that causes inflammation, that causes damage, that prevents OPCs from maturing into oligodendrocytes. So this is a very hot topic in the field of microglia and Ms. Research at the moment. And we think that if we can better understand that, we can develop new therapeutic strategies to support microglia to turning to that state that we want them to be in. That would in turn lead to better remyelination.

A (16:16)

Yeah, that's awesome. I think this is really important topic, Veronica, because we have a whole class of medications that's getting ready to launch BTK inhibitors. They affect B cells, but they also affect microglia. But if BTK inhibitors affect microglia, then the question is, is it going to be positive to preventing demyelination, or is it going to be inhibitory? So I think that's where the big question comes into play.

B (16:40)

One of the reasons why there's so much excitement about this class of drugs is that we don't currently have any drugs that are aimed at directly targeting microglia function, even though we know that the microglia are really important in influencing myelin health and remyelination. Now, why we think BTK inhibitors might be important is that the BTK protein is present at very high levels and in microglia, and that usually indicates that this protein has a really important function in these cells. We're still figuring out what BTK actually does in microglia, but it's thought that it controls inflammation. There's the hope that BTK inhibitors can act on microglia to reduce their turning into this damaging inflammatory state, and this could potentially be helpful for remyelination by removing this roadblock of this damaging inflammation. It's interesting that you mentioned that this might actually be able to influence demyelination once the demyelination has started, and then you're in this whole cycle of myelin damage and repair in Ms. Microglia in this damaging state might also contribute to worsening demyelination once it's already started. Now, there's also hope that these BTK inhibitors could prevent this damaging microglia state that contributes to demyelination, and particularly in progressive ms, when we have a lot more of these chronic lesions and we have these very angry microglia that are present in these chronic lesions. And so this is currently what's being tested. There are many different kinds of BTK inhibitors. Some are more potent than others, and some are better at getting into the central nervous system than others. So it'll be really interesting to see the difference between these BTK inhibitors and how effective they are in ms, in progressive ms, and whether they are primarily working through microglia to influence people with.

A (18:48)

Ms. One of the other things that's always been out there is you have these OPCs, and for some reason, it's hard to recruit them into the lesions. Any work on that in terms of the obstacles?

B (19:01)

Yeah. So There are really two main categories of roadblocks preventing OPCs from being recruited into the lesions. So one is that the way that OPCs are attracted to the lesions is by factors being released by cells within the lesion that are telling the OPC come into the lesion. It's like an attractive signal. And so if we're losing those, or if the cells in the lesions are making signals that actively repel the OPCs from coming into the lesion, that will prevent them from coming in. Another category of factors that will prevent OPCs from entering the lesion is if we have accumulation of myelin debris as a result of Demyelination in a lesion that will repair. Well, normally we have the macrophages. They are very good at eating up this myelin debris. If they can clear that myelin debris, that really clears the way for the OPCs to be able to come in. This myelin debris also contains signals that are actively repelling the OPCs out and also preventing the OPCs from maturing into oligodendrocytes. There's a lot of interest now in trying to find factors that can support macrophages to do a better job of clearing the myelin debris so that the OPCs can come into the lesion and mature into oligodendrocytes.

A (20:34)

I know there's been a few attempts over time, and we're going to talk about more of that with Dr. Glanzman. So from where you sit as a scientist, do you anticipate meaningful breakthroughs in remyelination research that can prove the lives of our listeners out there living with multiple sclerosis?

B (20:50)

In terms of big breakthroughs in the field, I think there's two things that would be really influential for people with Ms. The first would be to find a drug that can boost remyelination, even in aged individuals, which has been an ongoing challenge in the clinical trials. The second is to continue to develop a combination of readouts from the clinic that give us confidence that we are affecting remyelination. For example, this would include identifying a biomarker in the blood that would tell us that remyelination has been improved in people with Ms. Great.

A (21:28)

So you definitely sound optimistic that we could come up with a remyelinating compound.

B (21:32)

Absolutely. I think the clinical trials are really encouraging, and this field is pushing at a very quick speed, and I think we're going to get there.

A (21:40)

Well, thank you very much, Professor Marron, for joining the Ms. Living well podcast. It was a pleasure having you on, and thanks so much for educating Ms. Community.

B (21:48)

Thank you so much.

A (21:56)

My next guest is Dr. Robert Glansman. Dr. Glanzman trained in neurology at the University of Michigan, went on to specialize in diagnostic imaging at Duke, and then taught as an assistant clinical professor of neurology at Michigan State. After joining industry in 1990, he's held increasingly important roles at Pfizer, Novartis, and Roche, where he was responsible for the design of the global phase 3 clinical trials for Ocrevus for both relapsing and primary progressive Ms. More recently, Dr. Glanzman has held leadership positions at several biotech companies and is currently chief medical officer of find therapeutics. So Dr. Glansman welcome to the podcast.

C (22:39)

My pleasure to be here. Thank you very much for inviting me.

A (22:41)

Great. So let's talk about remyelination. Rob. Each nerve cell or neuron has one branch called an axon, which carries electrical signals to other neurons. That axon is normally wrapped in myelin, but in multiple sclerosis, at myelin, and sometimes the axon itself gets damaged. So the big question for you, Rob, is when we talk about repairing myelin, are we hoping to restore lost neurologic function? Are mainly to protect that axon and slow down disease progression.

C (23:10)

What we're trying to do is save the axons we can save, right? I mean, axons that are already kind of broken and severed. I think it's going to be a long time in the future before we can sort of regrow those. But currently, what we're doing now very well is to prevent the immune system from coming in from the body and attacking the brain. So if someone wakes up in the morning and their legs are numb and they have difficulty walking, and that takes a day or two to happen, and then it takes maybe two or three months to kind of recover from that, we call that a relapse or an attack. And that's really caused by the immune system coming in from your body and attacking your brain and spinal cord. But we're very good at preventing those. Now, what we're not very good at is preventing the slow worsening that we call progression. And part of that is because what's happening is that there's ongoing demyelination and lack of remyelination. And children are very good at this. But as we become adults, we lose that ability. So that's part of what we're trying to do here, is restore that childlike ability to repair the brain.

A (24:11)

So, Rob, there have been earlier attempts at remyelination, including trials I was part of using monoclonal antibodies such as elizanumab, opacinumab and rhigm 22. They look very promising in animal models, but unfortunately, they didn't deliver in people. What lessons came out of those experiences?

C (24:30)

The key lesson to be learned is that animal models are imperfect at best. The problem is that this is all we have. So if you've got a drug in development, you've got to test it in animal models. You're also going to establish the toxicity in animals. The FDA will allow you to test it in humans. You have to make sure it's safe in animals to use at much higher doses than you would ever use in a human. And once you've done that, then FDA will allow you to put it into human beings. But the problem is that we really have to try these drugs in humans before we really know if they're going to work or not. And that's a very expensive and time consuming process.

A (25:00)

I think one of the concerns too with the molecules that we have tried, these monoclonal antibodies, they're actually large molecules and antibodies don't get into the brain spinal cord in high concentration. So you're hoping a small percentage of that antibody actually gets into the nervous system to do what you want it to do.

C (25:16)

Yeah, that's exactly right. In fact, we have a blood brain barrier. Right. You have it for a reason. And the blood brain barrier does a lot of good things. It keeps the environment of your brain and spinal cord conducive to all this electrical activity that the brain and spinal cord have to generate. But on the other hand, it does keep out large therapeutic molecules. So it's kind of a double edged sword. There are some companies like Denali that are trying to develop these, these brain shuttle kind of technologies. I think it's a step forward. But again, for most companies, only about zero, half a percent of the injected dose gets to the brain. So 99.5% of your drug is, is not reaching the target. So that's a problem. But you know, we have to go with where, where we are.

A (25:56)

These approaches once looked quite promising. Take alizanumab. It targets a molecule called repulsive guidance molecule A. With the goal of improving remyelination and even promoting axon repair. We gave patients monthly infusions at our center for over a year. But unfortunately, there was no benefit in either relapsing or progressive Ms. Patients. Another antibody, opencinnumab, was designed to block a protein called lingo1, which normally prevents oligoprecursor cells from maturing into myelin producing cells. The hope was that by blocking lingo 1, these cells could finally make new myelin. But again, the trials and people ultimately failed.

C (26:36)

Yeah, no, exactly 5 to 10% of the cells in your brain and spinal cord are these immature cells that could become remyelinating cells. So it's not like the cells aren't there. But one of the problems is they don't really get into the lesions very well. And that's why these repulsive guidance molecules are becoming therapeutic targets. And in fact, the drug that I'm working on now called FTX101 is based off of work that was done in France based on the semaphoren system. So semaphore 3A is A, is a guidance molecule that's normally very active during embryology. So the brain sort of develops from this thing we call the neural crest, which forms the neural tube. And then all of the cells kind of migrate out of the ventricles from the neural tube, and they eventually form all the structures of the brain. And the way those cells migrate and where they go to their final resting place in a mature brain is all through guidance cues. And one of those major guidance cues is semaphore and IIA. And we know that semaphore and 3A in the adult brain is not very active at all. And we know from pathological studies that semaphore 3a becomes active in Ms. Lesions. So if you look at active lesions or even chronically active lesions, there are some of 4 and 3A there. And semaphore 3A, when it becomes active, it does a couple of things. Not only does it prevent these immature cells from becoming mature cells, it also prevents them from getting into the lesion. And so we think that there are repulsive guidance cues. Fibrinogen may be part of this. We think there's a kind of a repulsive milieu that's keeping these immature cells from going into lesions and myelinating. And the peptide that I'm working on now is designed to kind of go into the plasma membrane and break apart this receptor complex that I just described and prevent second messenger signaling.

A (28:13)

So that's pretty fascinating. Another approach has been looking at older medications. We actually had Ari Green on the podcast with the first season about seven years ago, and he was talking about some compounds that they've found that stimulate remyelination, basically in the lab, adding all these old compounds onto immature cells and seeing if they can form myelin making cells. So a couple of these older compounds like clemastine and metformin, Foreman have been shown to do some remyelination. So what's your approach there?

C (28:46)

Arie's a very bright guy. They did a lot of cell culture work to look and see what promotes remyelination, and that's really a smart way to go. What they found was this drug called clemastine, which is really antihistamine. So clemastine originally is an antihistamine. It's just used for people with colds, but it's a pretty dirty drug. So it affects the histamine receptors. It also affects what's called a muscarinic receptor, part of major excitatory neurotransmitters in the brain, these certain type of muscarinic receptors called M1 receptors inhibit remyelination. And so Clemastein also was a blocker. It actually promoted remyelination. And he did a study at ucsf, which is a very reputable institution. He did a crossover trial where he gave people either placebo or clemastine, and he added it onto their current therapy. So just to take a step back a little bit, any drug that you're going to give for myelination, you're going to have to inhibit the inflammatory process first. If you stop the therapy that people are using to prevent their attacks, they're going to have attacks, and the brain's going to be inflamed. So you have to stop the inflammation first. But once you've done that, then you can add a remyelinating drug. So he added Clevestein on top of people's standard of care versus placebo. He did it in a crossover fashion. First he gave people placebo, and then he randomized other people to clemaine. And then after a while, he stopped it, and then he switched them. I think he washed them out for a couple weeks, and then he switched them. So the people that originally got placebo got active. And there were people who originally got active got placebo. So it's called a crossover study. What he showed was based on something called visual evoke potentials, which is a very sensitive way of looking at how well the myelin is functioning in the visual system. So basically, the way those work is you flash patterns of light in front of people's eyes, then you wait to see how long it takes that signal to get back to the part of the brain that controls vision, which is called the occipital lobe. So what he showed was that if you give people clemastine, that you can actually reduce the latency of the signal compared to placebo, which is showing that you're improving the myelin integrity of the visual pathway. He also showed that people that got clemastein, their vision improved compared to people that got placebo. So that's pretty strong data. And based on those data, they actually formed a biotechnology company. They got a more potent and specific M1 receptor antagonist.

A (31:01)

Pipe 307.

C (31:02)

There you go. And they're partnering that with J and.

A (31:04)

J. Yeah, that's in phase 2 clinical trials. It's kind of interesting because, again, you mentioned this, M1, a muscarinic receptor. So this receptor that's on the surface of these cells, it was developed based on green mamba snake venom.

C (31:18)

Yeah, there you go.

A (31:19)

So green mamba snake venom binds onto the Zen1 muscarinic receptor. But it looks like if you can block this receptor, you can stimul remyelination pretty dramatically. So that's in phase 2 clinical trials. So some hope there that maybe we'll have a compound that can stimulate those receptors.

C (31:36)

Absolutely. That would be great.

A (31:37)

The one downside with Clemastein is it's pretty sedating. The other one that has some interesting data is metformin, which is used for diabetes. But if you're not diabetic, we don't want to bottom out. Your blood sugar, it can cause diarrhea. So you could cause yourself some harm by taking metformin if you're not diabetic.

C (31:54)

All drugs have side effects. Aspirin kills thousands of people every year. Right. Even though it's been used for centuries. And I think if you're a person living with a chronic illness, you have to think about the risk benefit ratio always.

A (32:05)

Yeah. We are collecting much more data on these drugs. Clementine and metformin are going forward. There's more clinical trials. It was just on clinicaltrials.gov and I could see there's more work going. So we'll stay tuned for that. I wouldn't jump on that yet, but it's coming.

C (32:18)

Yeah.

A (32:19)

So let's move on to gold nanoparticles. One of the reasons why I had you on the show is we've seen a lot of development in the world of remyelination, but not as fast as people out there would like. I have many patients that say, I need this in two years. So you got two years to get this together, Singer. So, you know, my patients are on me.

C (32:40)

That's a tough crowd, buddy.

A (32:42)

And so one of the things you worked on previously to the company that you're on now is gold nanoparticles for remyelination. So what's the scoop with gold nanoparticles?

C (32:51)

I was the chief medical officer for what's called Clean nanomedicine. That's the name of the company, Clean Nanomedicine. I was the chief medical officer there for four years from 2019 to 2023. And we ran a phase two study of these gold nanoparticles in people with Ms. It was called Visionary Ms. It was done mostly in Australia. The way this works is there's a guy named Mark Mortensen who's one of the co founders of Clean. He's a physicist, and he figured out a way to make gold atoms self aggregate into crystals in Highly purified water. It's pretty cool. If you go to the manufacturing facility in Maryland, what you'll see is they have these clean rooms, and then you'll see these troughs with water running through the trough. And you'll see gold wires in the trough. And then you'll see these flashes where he induces plasma right over the water, which breaks apart the water molecules and causes them to ionize and have a lot of energy. And then it runs across these gold wires, and the gold wires slough off individual atoms, which then circulate around the gold wires and end up forming crystals. So if you have a million parts of water, you've got seven gold nanocrystals inside of them that kind of runs down into a container, and then they evaporate off the water. And then what you're left with, it's a very stable suspension of gold nanoparticles in highly purified water. That's the product, and it's really cool. One of the problems that clean has is that nobody understands how it works, but what it does in multiple animal models, cells that are not functioning very well having difficulty making energy. These gold nanoparticles allow those cells to make energy. That's really what's going on.

A (34:29)

Okay, that's super interesting. So how do you get gold nanoparticles in your body?

C (34:34)

You drink it. So it's pretty cool. I mean, you're basically drinking water.

A (34:37)

Excellent. So let's move into future remyelination compounds. You talked a little bit about the compound that you've been working on. Any other compounds that you're also excited about?

C (34:47)

I think the good news is there's a lot of work going on. The bad news is, right now, getting somebody to pay for your development program when you're a small company is a nightmare, because given the political environment, the current financial environment, investors are not willing to take risks. Again, there's a lot of work being done. Right now there's a guy named Robin Franklin in the UK who's looking at fibrinogen. So I think we're trying to do our best to sort of block these inhibitory factors that we know are there and see if that's going to promote remyelination. But again, right now, getting funding for a development program, you know, is very, very difficult.

A (35:21)

Are there other challenges that you see besides the funding?

C (35:24)

It's probably a combination of things. We have to remove the factors that are inhibiting the cells from becoming immature. We also have to give the cells enough energy. To do that, you have to Remove the inhibitory factors that are there and then you have to inhibit the ongoing inflammatory process throughout the brain. So it's a pretty complicated process. And then even if you have a drug that actually remyelinates, how do you prove it?

A (35:44)

Yeah, important point. People have been working on ways of imaging remyelination so that we actually can see the changes on MRIs.

C (35:51)

Absolutely. So there's a couple of ways that we can show remyelination in the brain. One of them is with imaging, something called diffuser tensor imaging, which is a way of imaging myelinated axons. Another thing called magnetization transfer ratio imaging. There's myelin water imaging. There's all kinds of imaging methods that we can use to show intact myelin in the brain. And then visual evoke potentials are also very, very sensitive and also very specific to myelin integrity. The problem is that FDA is not going to give you an approval based off of imaging or electrophysiology. They only will give you an approval based off of what they call clinical improvement. And so that's the difficulty because the way we do it now is pretty inefficient and very costly and time consuming.

A (36:32)

So for people living out there with Ms. And all us neurologists taking care of people with ms, how can we better advocate to propel remyelination research forward?

C (36:41)

Well, look, I think given the current political environment, I would call my representative and say we have to fund basic science research first of all, and we also have to fund clinical research. Right. We need to do a better job than we're currently doing at Health and Human Services of funding research, that's for sure.

A (36:55)

Yeah, I totally agree. Well, thank you so much, Dr. Glanzman, for giving all your insights on remyelination. Do you have a realistic time frame when we may see the first compound on the market? What do you think?

C (37:06)

Unfortunately, it's a long and tedious process. Certainly for my compound we have to do the phase two, which we won't start until 2027. Now we're doing a PET imaging study first to show that it actually goes into the brains of people with Ms. Then, you know, phase three can't really start until 2029, maybe 2030, and then you're looking at three to five years to do a phase three program. So that's how it works. So 2033, we may have a remyelinating drug on the market.

A (37:30)

Wow. So a little longer than we anticipated there, Rob. But we'll keep pushing ahead on that. So thank you very much, Rob, for joining the Ms. Living well podcast. I appreciate all your efforts in the world of Remyelination.

C (37:43)

Well, thanks for inviting me Dr. Singer. It's a real pleasure and honor to have been asked.

A (37:55)

Thanks to our listeners for downloading this episode of the Ms. Living well podcast. Repairing Ms. The Quest to Rebuild Myelin Many thanks to Professor Mirrom and Dr. Glanzman for sharing their work to make remyelination a reality. The cells needed repair myelin are already in the brain and spinal cord just need the right treatments to unlock their potential. The road is long but the progress is real and the hope of restoring function for people living with Ms. Has never been closer. Thanks again to TG Therapeutics for sponsoring this episode. Keep in mind the topics we discuss on the show are strictly informational and not medical advice. Any change in your treatment should be discussed directly with your healthcare providers first. Our show is hosted by me, Dr. Barry Singer and Dr. Jamie Holloman and produced by Kerriette Harmon. Our theme music is the Gold Lining by Brook for free. If you like the show, please share it with others living with multiple scroses. And when you get a chance, please post a positive review on Apple Podcasts. It really helps more people find out about the show. You can follow me on X at Dr. Barry Singer and Dr. Jamie Holloman at BrainBoyNeuro. 1. More information about our guests and the websites can be found in the show notes for this episode in the blog section on mslivingwell.org thanks so much for listening. This has been an Ms. Living well podcast.