Combination-Based Drug Screening for Induced Oligodendrocyte Differentiation Enables Mechanistic Insight and Identifies Optimal Drug Pairs for Remyelination

Abstract

Remyelination-promoting agents have significant potential utility as therapies for the treatment of demyelinating diseases, including multiple sclerosis. Clemastine and bexarotene have recently been evaluated in Phase II clinical trials to evaluate their potential in this context, with evidence for drug-induced remyelination being observed in both trials. Efficacy levels for both agents as monotherapies, as well as dose-limiting toxicities, highlight the need for more effective approaches. Additionally, questions about the relevance of M1R as the target of clemastine, and also around a mechanism involving accumulation of 8,9-unsaturated sterols, remain. Here, we have identified potent alternatives to clemastine (i.e., doxepin and orphenadrine), which are predicted to have superior tolerability and efficacy profiles and provide mechanistic insight related to M1R, and have completed pairwise drug combination screens using diverse classes of OPC differentiation-inducing agents. Vitamin D receptor agonists were found to enhance M1R antagonist-induced OL differentiation. Select compounds implicated in 8,9-unsaturated sterol accumulation synergistically enhanced the activity of bexarotene in OPCs, which resulted in insights that implicate a critical role for liver-X-receptor in the mechanisms of both sterol-dependent and bexarotene-induced remyelination.