Remyelinating Pharmacotherapies in Multiple Sclerosis

Abstract

We have witnessed major successes in the development of effective immunomodulatory therapies capable of reducing adaptive immune-mediated myelin damage in MS over the last 30 years. However, until it is possible to prevent MS or initiate treatment before it has already caused lesions there is a need to repair myelin damage to prevent further axonal loss. The past decade has brought remarkable advances in our understanding of oligodendrocyte biology and the related search for remyelinating therapies in humans. In this review, we first outline the basic biology of central nervous system myelin and remyelination, including a discussion of the major identified pathways and targets that might help yield CNS remyelinating drugs. In conjunction, we provide an overview of techniques that have helped identify compounds capable of promoting oligodendrocyte precursor cell differentiation and myelination. This includes the methods for both initial in vitro screening and subsequent in vivo confirmation of the target. We then review methods proposed to quantify human remyelination in vivo, including visual evoked potentials and putative imaging modalities. As the remyelination era approaches, with the announcement of the first positive trial in remyelination, we are now tasked with answering new questions regarding patient-specific factors (e.g., age) that may influence the extent and optimal therapeutic window for remyelination.

Keywords: Clemastine; LINGO1; Multiple sclerosis; Muscarinic; Neurodegeneration; Remyelination.

Fig. 1

Remyelination. Oligodendrocyte precursor cells (OPCs) undergo maturation to oligodendrocytes, which then wrap myelin around demyelinated axons. At each step, the remyelination process may be promoted or inhibited by intrinsic and extrinsic signals or by environmental cues (adapted from [40] and [107]). NSC = neural stem cell; OPC = Oligodendrocyte precursor cell; OL = Oligodendrocyte; PSA-NCAM = polysialylated neural cell adhesion molecule; MYRF = Myelin Regulatory Factor