An multiple sclerosis expert shares his thoughts on enhancing myelin regeneration and repair to counteract neurodegeneration in patients with multiple sclerosis.
Robert Zivadanov, MD, PhD: My talk was part of a bigger course on remyelination and repair that I was sharing with 3 other speakers or co-hosts at the meeting. During this symposium, we tried to cover all aspects that are relevant to detect remyelination in MS. One of the first big points is, what are the characteristics of myelin and why is the remyelination in many cases is not optimal? One thing that was presented by Dr. [Wee] Yong, PhD, was talking about factors that can impede or inhibit myelination. That’s a very important topic because you can have great techniques to detect it, but if you don’t know which factors are decreasing the remyelination capabilities of the CNS [central nervous system], you’re not going to develop the drugs. Clearly, one big area of theremyelination discussion is to target different mechanisms of actions within which you can promote remyelination. I think that was covered in all 4 talks.
The other is creating techniques and designs of the studies that can cover potentially different aspects of remyelination. In general, there are two big models on how you can start the remyelination, both preclinical and clinical models. The preclinical models have been extremely helpful because most of the experiments so far have been conducted in this model. That is, TMV toxin models, including cuprizone, and in-vitro assays of oligodendrocytes that identified many relevant molecules.
The clinical outcomes are based on a couple of regions, one being the optic nerve or on the lesions themselves. In that context, lesions or normal appearing white and gray matter are usually the target of demonstrating demyelination and then the electrophysiology biomarker, especially for the visual system. This includes multi-evoked potential in optical coherence tomography. Clearly what the FDA is trying to see is also clinical biomarkers. Usually, the composites of Expanded Disability Status Scale, walking, and N-function, as well as cognition, has been incorporated in these trials.
The design of these studies could be short term, maybe 3 to 6 months, in which you’re comparing placebo to a treatment group. Or a very popular crossover design where you have half of the patients doing the treatment for the first 6 months and then switched to placebo, and vice versa for placebo to treatment group. There have been studies with running periods where you see how a patient would do without adding myelination treatment and then you add-on remyelination treatment. All these treatments have 2 goals: to slow down continuing progression and disability, or improve existing disability, which is the ultimate goal. That’s where the remyelination would be in a true sense of the word.
The FDA is looking more on clinical outcomes for approval, but it seems that based on the some of the studies, this is unrealistic at this time. It takes 2 or 3 years to prove, which is maybe not enough time. Maybe these trials need to be used in a longer clinical component, probably up to five years. In my presentation, I discussed a history of how we evolved in terms of developing these MRI measures over time. Both preclinical as well as clinical studies taught us how some of these outcomes are useful in predicting remyelination. In general, conventional MRI measures like T1 or T2 are not very useful in recognizing which are lesions or even part of the tissue remyelinating or demyelinating.
Two substantial approaches have been developed in the last 15 years. One is to work on myelin sensitive techniques. This includes magnetization transfer ratio, myelin water fraction, and quantitative MTI. The second pool of techniques is based on diffusion tensor imaging. Those include fractional and are a result of radial diffusivity, axial diffusivity, and mean diffusivity. In the last couple of years, DTI has undergone a number of improvements. In addition to these simple metrics that I mentioned, NOTI, which is narrower, right, dendritic density imaging, has been embraced by many people. You can now obtain these so-called fractions of water versus axons or versus myelin. This myelin water fraction and axonal water fraction are much more sensitive to changes in the myelin or changes in the axons.
What I presented is this novel approach, which has been used in the histology studies of determining the G ratio. You first determine the myelin water fraction, axonal water fraction, but then you go and use information from both to determine whether its predominately myelin changing or axonal. In a case where the myelin water fraction would be decreasing while axonal is stable, then the duration would increase. That would mostly be myelinating. Or, if the remyelination is appearing, just the opposite.
On the other hand, if the axonal is predominant, then you will say, "wow, that’s not due to demyelination." This approach has never been done in a clinical trial of remyelinating drugs so far, but it’s extremely promising. That’s why it also requires high level scanners and protocols that cannot be done in a standard clinical routine care, which is why these types of trials are important to the optimization and standardization.