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.

Nanocatalytic activity of clean-surfaced, faceted nanocrystalline gold enhances remyelination in animal models of multiple sclerosis

“…There are other remyelinating agents in various stages of clinical development, including opicinumab, an anti-LINGO monoclonal antibody; elezanumab, an anti-RGMa monoclonal antibody; NDC-1308, an estradiol derivative; and clemastine fumarate, an older generation antihistamine and M1/M3 muscarinic receptor reverse antagonist (36)(37)(38). Remyelination is a complex process involving multiple intrinsic and extrinsic signals to the OL (37). Accordingly, these therapies work by blocking inhibitory signaling pathways, or by stimulating positive signaling pathways, of OPC differentiation (38)(39)(40).…”

Leukemia inhibitory factor inhibits erythropoietin-induced myelin gene expression in oligodendrocytes

“…antibodies to LINGO-1) or provide positive stimulation (e.g. clemastine fumarate) are in the translational pipeline, but no remyelinating drugs are currently available (Kremer et al, 2015 ; Cadavid et al, 2017 ; Green et al, 2017 ; Bove & Green, 2017 ).…”

White Matter and Neuroprotection in Alzheimer’s Dementia

“…Screening for targets of remyelination, and molecules acting on these processes, seems to be the most widely used drug discovery strategy, based on isolated primary OPCs, embryonic/ neural stem cell-derived OPCs, or induced pluripotent cell-differentiated OPCs, all cell systems which allow a molecular analysis of the physiological OPC differentiation process [85,86]. As we are learning from MS, however, pathological conditions interfere greatly with physiological mechanisms and the microenvironment where OPCs undergo differentiation/maturation processes, highlighting the need to develop new strategies based on pathological in vitro and in vivo models [53]: One such example emerged from a pharmacological strategy developed to save neurons from cell death, based on the inhibition of the poly(ADP-ribose) polymerase (PARP).…”