Drug discovery for remyelination and treatment of MS

Abstract

Glia constitute the majority of the cells in our nervous system, yet there are currently no drugs that target glia for the treatment of disease. Given ongoing discoveries of the many roles of glia in numerous diseases of the nervous system, this is likely to change in years to come. Here we focus on the possibility that targeting the oligodendrocyte lineage to promote regeneration of myelin (remyelination) represents a therapeutic strategy for the treatment of the demyelinating disease multiple sclerosis, MS. We discuss how hypothesis driven studies have identified multiple targets and pathways that can be manipulated to promote remyelination in vivo, and how this work has led to the first ever remyelination clinical trials. We also highlight how recent chemical discovery screens have identified a host of small molecule compounds that promote oligodendrocyte differentiation in vitro. Some of these compounds have also been shown to promote myelin regeneration in vivo, with one already being trialled in humans. Promoting oligodendrocyte differentiation and remyelination represents just one potential strategy for the treatment of MS. The pathology of MS is complex, and its complete amelioration may require targeting multiple biological processes in parallel. Therefore, we present an overview of new technologies and models for phenotypic analyses and screening that can be exploited to study complex cell-cell interactions in in vitro and in vivo systems. Such technological platforms will provide insight into fundamental mechanisms and increase capacities for drug-discovery of relevance to glia and currently intractable disorders of the CNS.

Myelination and mTOR

“…Based on (a) the metabolic challenge endured by myelinating cells during development (Forbes & Gallo, 2017; McKenzie et al, 2014); (b) the requirement of a regular supply of myelin components in adult life (in homeostasis and during adaptive myelination) (Bechler & Ffrench‐Constant, 2014; Gibson et al, 2014); and (c) the central role of remyelination after injury and in disease (Cole, Early, & Lyons, 2017), signaling pathways central to cell metabolism are likely to occupy strategically relevant positions in the regulation of myelination in health and disease. Among such pathways, we will focus in this review mainly on the role of mTOR and closely associated signaling components.…”

Unravelling the glial response in the pathogenesis of Alzheimer's disease

“…The myelin sheath maintains the action potentials and ion currents in the axons, thus reducing energy consumption and increasing conduction velocity, whereby a myelinated axon is more efficient at transducing a signal than an unmyelinated one (124). The disruption of oligodendrocyte function has been implicated in a number of disorders, including AD, PD, multiple sclerosis, and cerebral palsy (reviewed elsewhere (125)(126)(127)(128)]. Any event that targets oligodendrocytes will invariably result in demyelination.…”

Mechanisms of lysophosphatidylcholine‐induced demyelination: A primary lipid disrupting myelinopathy

“…Therefore demyelination is associated with axonal injury, and impairing remyelination may enhance such injury (Irvine and Blakemore, ). For these reasons, there is much ongoing research to find medications to promote or accelerate remyelination (Cole, Early, & Lyons, ; Franklin and Gallo, ; Marriott et al, ; Plemel, Liu, & Yong, ). One model that is often used to study remyelination is the injection or bath application of lysophosphatidylcholine (LPC or lysolecithin) into white matter tracts (Jarjour, Zhang, Bauer, Ffrench‐Constant, & Williams, ).…”