In this podcast, Dr Coyle discusses the "final word" on strategies to promote remyelination in multiple sclerosis from the ECTRIMS/ACTRIMS MSVirtual2020 meeting.

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Patricia K. Coyle, MD, is a professor in the Department of Neurology at Stony Brook University in New York; director of the Stony Brook MS Comprehensive Care Center; and section editor of multiple sclerosis on Neurology Learning Network.

Transcript:

Christina Vogt: Hello everyone, and welcome back to another podcast. I'm Christina Vogt, managing editor of Neurology Learning Network. Today, I'm joined by Dr Patricia K. Coyle, who is a professor of neurology and director of the Stony Brook MS Comprehensive Care Center at Stony Brook University in New York.

Today, Dr Coyle will be sharing the ‘final word’ from MSVirtual2020 on strategies to promote remyelination in multiple sclerosis.

Patricia K Coyle, MD: Let's discuss strategies to promote remyelinization from MSVirtual2020. This is a very hot topic because, quite frankly, we don't have any CNS repair strategies, and one major focus of CNS repair is remyelinization because when myelin is stripped off the axon, it doesn't just disrupt nerve conduction. There's a symbiotic relationship, and it really does harm the axons.

So we're beginning to learn more about this, and it's interesting. We're reporting this podcast in the setting of just having heard that opicinumab, the humanized anti-LINGO-1 monoclonal antibody, has failed its remyelinization study unfortunately.

So there were some very interesting basic science studies on remyelinization at this virtual meeting, and it was fairly prominent that really pointed towards a role for the astrocyte. The astrocyte is one of the glial cells, as you know, in the central nervous system. It makes up the highest proportion of cells, and it appears that astrocytes can either support or impede CNS remyelinization.

They're not the cells that make the myelin. It's the oligodendrocyte that makes the myelin, but apparently, the astrocyte is very important. They documented changes in the astrocyte in a so-called translatome of the astrocyte during remyelinization periods, and they found that genes were being upregulated and downregulated.

So, I think there's going to be greater focus on what exactly is the role of the astrocyte in boosting remyelinization or not supporting it, blocking it, and are there things that we can do to target the astrocyte to promote it?

So two – they found the Nrf2 oxidative stress pathway may also play a role in remyelinization, and there may be important molecular switches that manipulate that stress pathway to promote or block remyelinization, and that's going to be another new focus of study because it would suggest novel potential treatment targets.

They also mentioned the cholesterol biosynthesis pathway and enrichment of that as a factor in remyelinization, and so we're beginning to identify targets we would never have thought of initially being involved in remyelinization. People are going to be looking at them to determine whether there are some therapeutic targets that would be helpful.

There was also discussion in the remyelinization talks and abstracts about the importance of age. Remyelinization seems to be maximum early before age 40, and you really don't want to delay a long time. It seems to be age may be a very important determinant in remyelinization repair, and you'd like to be younger rather than older, better under age 40.

They're looking at drugs that promote differentiation of oligodendrocyte precursor cells or OPCs and what are new drugs that can be identified, and this was a basis of clemastine that's currently in testing as a remyelinating-CNS-repair strategy.

Very interesting work with calorie restriction–they found that if you fasted animals (this is in animal models) –if you fasted them, they started to respond like young animals, and you were able to see remyelinization.

There's a mimetic metformin that has actually had some studies and was being touted as a potential remyelinization, calorie restriction-related-type agent to boost remyelinization. They're looking at aging and what controls aging.

So for example, in an animal model, they looked at progenitor cells, and the aged progenitor cells don't divide and proliferate. Well, they took these aged progenitor cells, and they transplanted them into a developing brain. Lo and behold, they transformed. They were acting like young progenitor cells. They started to divide and proliferate, really indicating the environmental niche was completely controlling the progenitor cell.

It wasn't that it was really old, even though it was an old progenitor cell. If you put it in a new environment, if you put it in a young microenvironment, it would act like a young progenitor cell, and that's a very interesting concept.

Another thing they pointed out was that the brain actually gets stiffer with age. There are mechanical property changes. It gets stiffer with age. Well, is that a factor, and can we block that? Can we prevent that? Can we stop the brain from getting stiffer with age? Very interesting.

There was also a phase 2 trial reported at this meeting of a new agent that was looked at as a remyelinating agent. This was a phase 2 trial that tested retinoid acid X receptor agonist, a gamma agonist. The name of the drug is bexarotene. It's an oral agent available for cutaneous T-cell lymphoma.

Well, this is an agent that, in models, promoted OPC differentiation and remyelinization. This was a double-blind, placebo-controlled trial that entered 52 relapsing patients on dimethyl fumarate, and they took orally 300 mg/m² of bexarotene vs placebo.

Now, this was a sophisticated study. How do you measure remyelinization? They use magnetization transfer ratio, or MTR. They measured it at baseline in all of the lesions. They took the mean value and took the lesions that were lower than the mean value, and so they were looking for a positive increase in MTR in those lesions.

In addition, they looked at visually evoked potential latency. Well, the first thing they found–the primary outcome, which was the MTR change, in these 50% of lesions that were below the average MTR value–it was not met. It was not statistically significant, so that's a negative study.

But when they looked at the lesions that were above the average MTR, they actually showed improvement and increase in the MTR, and they also found a decrease in visually evoked potential latency, suggesting there might actually have been a promotion of remyelinization.

Unfortunately, this particular agent was very, very poorly tolerated. Twenty percent of the cohort had to discontinue, and 48% had to have a dose reduction, and things like hypothyroidism developed in 100%, increased triglyceride, rash, and neutropenia.

This will be abandoned. This will not be taken further, but it's an interesting study that seemed to validate the concept of looking at MTR, and so really, stay tuned for that further.

I would just mention 2 other brief studies. One of them was in the cuprizone model of demyelinization. That's an animal model. It's a neurotoxin that causes death of oligodendrocytes when it's fed to mice. It lasts 5 to 7 weeks, and then there's spontaneous remyelinization after the animals are 4 weeks off the cuprizone poison that they were given.

So, this was a cuprizone model, and they also had some biopsy and pathology studies, and what they found were that satellite oligodendrocytes in the gray matter that typically are giving more metabolic support, do not remyelinate–seemed at least in early MS and in the early animal model to be capable of remyelinating, and they were remyelinating lesions within the gray matter. So, that's interesting.

Then the very final study I'll mention was a cuprizone animal model, and they looked at transcranial direct current stimulation or placebo. The animals got it for 5 consecutive days, and they saw an improvement, faster recovery in motor function with the direct current stimulation to the central nervous system vs the animals that had the placebo.

So, stay tuned because there are ongoing studies in humans that are looking at current stimulation to try to boost remyelinization.

Christina Vogt: Thank you again for joining me today, Dr Coyle. For more podcasts like this, visit neurologylearningnetwork.com.   

References:

1. Strategies to promote remyelination. Talks presented at: ECTRIMS/ACTRIMS MSVirtual2020; September 11-13, 2020; Virtual.
2. Brown W. Phase 2 clinical trial evidence that a retinoid-X receptor agonist promotes remyelination in people with relapsing-remitting multiple sclerosis. Paper presented at: ECTRIMS/ACTRIMS MSVirtual2020; September 11-13, 2020; Virtual.