Re-myelination strategies in MS still pose many unanswered questions

A large amount of preclinical and clinical research has been dedicated to re-myelination in MS, with limited positive results. Possible explanations could include the wrong choice of targets, study populations, and/or markers.

For over 30 years, Prof. Catherine Lubetzki (Sorbonne University, France) has focused on studying re-myelination in MS, but thus far few studies yield any positive results [1]. Generally speaking, there are 2 strategies to promote myelin regeneration: exogenous and endogenous re-myelination. Exogenous re-myelination involves the transplantation of neural stem cells that have the potential to re-myelinate. Thus far, only 1 such study was performed in MS patients: a prospective, exploratory, open-label, phase 1 study (NCT03269071) of intrathecal transplantation of foetal-derived neural stem cells in patients with progressive MS. The study has been completed, but no results have yet been published at the time of the ECTRIMS 2022 meeting.

Endogenous re-myelination uses strategies to promote spontaneous re-myelination, which in MS is normally insufficient after a few years. A preclinical, proof-of-concept study showed that semaphorin 3F-transduced haematopoietic stem cells stimulated migration of oligodendrocyte progenitor cells [2]. “This is an important concept, showing that macrophages can be used as cellular vectors to deliver pro re-myelinating agents at the right place and at the right time,” said Prof. Lubetzki.

Prof. Lubetzki went on to show that numerous drug trials with the aim of promoting re-myelination for the most part failed to meet their objectives. Among the agents that have been or are currently tested, are bexarotene, opicinumab, clemastine, bazedoxifene, and gold nanocrystals. Possible explanations for the negative results could be an incorrect choice of study targets, populations, and/or markers in these studies, or an insufficient number of preclinical studies with functional outcomes.

There is a need for more markers to monitor re-myelination and more primary outcomes. “We should also think very carefully about the selection of patients,” said Prof. Lubetzki. “I think we can agree that it is not useful to include patients with primary progressive MS, because they have too much axonal pathology. Instead, we should focus on relapsing-remitting MS and optic neuritis. We should include patients under 45 years of age, who have had the disease for less than 5 years, and perhaps focus on good re-myelinators.” Optic neuritis patients are an interesting group, since re-myelination and neuroprotection can be assessed by using spectral-domain optical coherence tomography and visual evoked potentials. “But is optic neuritis the same thing as MS?”

PS: For this last topic, see also the piece on optic nerve lesions as a fifth element for dissemination in space in MS, in the chapter on diagnosis and prediction of disease course.

1. Lubetzki C. Towards promoting remyelination in clinic. Scientific Session 3: Remyelination, ECTRIMS 2022, 26–28 October, Amsterdam, the Netherlands.
2. Aigrot M-S, et al. EMBO Mol Med. 2022;14(8):e14759.

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Posted on 20 December 2022