A large amount of preclinical and clinical research has been dedicated to remyelination in MS, with however limited positive results. Possible explanations could be the wrong choice of targets, study populations, and/or markers.
For over 30 years, Prof. Catherine Lubetzki (Sorbonne University, France) focused on studying remyelination in MS [1]. At her presentation, she pointed out that few studies thus far yield any positive results.
Generally speaking, there are two strategies to promote myelin regeneration: exogenous and endogenous remyelination. Exogenous remyelination involves the transplantation of neural stem cells that have the potential to remyelinate. Thus far, only 1 such study was performed in MS patients: a prospective, exploratory, open-label, phase 1 study of intrathecal transplantation of fetal-derived neural stem cells in patients with progressive MS (PMS). The study is completed, but no results have been published yet.
Endogenous remyelination uses strategies to promote spontaneous remyelination, which in MS is normally insufficient after a few years. A preclinical, proof-of-concept study showed that semaphorin 3F (Sema3F)-transduced hematopoietic stem cells (HSCs) stimulated migration of oligodendrocyte progenitor cells (OPC’s) [2]. “This is an important concept, showing that macrophages can be used as cellular vectors to deliver pro-remyelinating agents at the right place and at the right time,” said Prof. Lubetzki.
Prof. Lubetski went on to show that numerous drug trials, with the aim of promoting remyelination, have been done, but for the most part failed to meet their objectives. Among the agents that have been or are currently being tested, are bexaroten, opicinumab, clemastine, basedoxifene, and nanochrystal gold. Possible explanations for the negative results could be that the targets, study populations, and/or markers were wrong in these studies or the insufficient number of preclinical studies with functional outcomes.
There is a need for more markers to monitor remyelination and more primary outcomes. “We should also think very carefully about the selection of patients. I think we can agree that it is not useful to include patients with PPMS, because they have too much axonal pathology. Instead, we should focus on RRMS 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 remyelinators,” explained Prof. Lubetzki. Optic neuritis patients are an interesting group since remyelination and neuroprotection can be assessed by using spectral-domain optical coherence tomography (SD-OCT) and visual evoked potentials (VEP). “But is optic neuritis the same thing as MS?” she concluded.
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