Dr Ari Green Describes Remyelination Benefits for Patients With MS, Challenges of Trials

Ari Green, MD, chief of the division of neuroimmunology and glial biology at the University of California, San Francisco, details the benefits of remyelination for patients with multiple sclerosis (MS). He also discusses the challenges faced when conducting remyelination trials.

Green went into further detail on the topic on March 1 at the Americas Committee for Treatment and Research in MS (ACTRIMS) Forum 2024 during the session titled "Barriers to Neural Repair."

Transcript

Could you please explain the benefits of remyelination for patients with MS?

In MS, demyelination is a driving factor that is a part of the biology of the disease. Loss of myelin of a previously myelinated axon is a threat to that axon and leads to axonal degeneration and death. We don't know exactly how much you need to remyelinate an axon in order to keep it alive, but what we have identified is that when we remyelinate an axon, there's significant evidence, both in animal models and now in human subjects, that there are features that are suggestive that axons get preserved and kept alive; that's probably the most important.

Secondly, and it could be equally important, may turn out to be more important even than axon survival, is that neurological function emerges from complex circuitry that exists in the central nervous system. The nervous system is composed of 86 billion neurons with a huge number of interconnections between those neurons. The complexity of the circuits that exist is a driving force behind the emergence of normal neurological function.

When those circuits get disrupted, we've got a lot of work to do in order to restore them, and we see that circuits get disrupted with demyelination, but we're beginning to get evidence that those circuits get restored in the context of remyelination. That's particularly the case for the complex interconnectedness that is related to how synapses are connected between neurons and allow for transmission of signals that are highly timed and highly coordinated throughout the central nervous system.

What are the primary challenges or barriers faced in conducting remyelination trials?

First, it's identifying drugs that appear to show promise and doing lots of preclinical work in order to get those drugs to the point where we feel confident that they're likely to be effective. Beyond that, though, it's also the challenge of the measures. Which measures will we use? Which measures are both going to be convincing to us as researchers as well as convincing, ultimately, for new drugs, to regulators and are going to be important for patients? Are we going to show that remyelination? Are we going to have enough evidence that we all feel comfortable that this is going to lead to an improvement in the quality of life for patients?

The biggest barriers are those factors, all those factors, though, together. You have to do all the preclinical work, you have to do all the confirmation, then you have to test it in human subjects and ensure that it's safe and make sure you have these tests that exist that allow us to assess whether or not a drug works; that's all very expensive.

Another barrier is just cost and making sure that we have enough resources in order to be able to test a wide array of medicines because we wouldn't test them if, going in, we knew 100% they were going to work. We have to test them with some questions about whether or not they will work, and, of course, anyone who invests money in that space wants to see drugs that work. We're all disappointed when they don't, but a super important component is making sure we have adequate investments to get drugs on target that have the effect we need.