In silico screening and preclinical validation identify bavisant as a therapeutic candidate for multiple sclerosis

Abstract

Current treatments for multiple sclerosis (MS) are insufficient to delay the neurodegenerative process that is the main cause of disability progression in patients with MS. Therapeutics aimed at supporting myelin regeneration and neuroprotection are thus a major unmet medical need for the progressive forms of MS. To address this, we developed a strategy combining in silico screening of more than 1500 repurposed compounds with a validation pipeline of models, encompassing rodent and human in vitro assays as well as mouse models of demyelination/remyelination. From the initial library, 273 drugs were prioritized in silico on the basis of the predicted effects on myelination and neuroprotection, and among them, 160 were potentially nontoxic. We identified 32 molecules that exerted a promyelinating and a neuroprotective action on rodent and human oligodendroglia and neurons. Our data identified classes of compounds with potentially distinct mechanisms of action that may foster remyelination and neuroprotection. The therapeutic activity of one selected drug, the histamine receptor H3 antagonist bavisant, was further validated in mouse models of demyelination and axonal injury reproducing some key pathological features occurring in MS. Our in vivo studies demonstrated that bavisant promoted remyelination and neuroprotection when administered to LPC-treated, cuprizone-fed, or MOG-induced EAE mice, as well as in a human oligodendroglia chimeric mouse model of demyelination/remyelination. These findings provide proof-of-concept validation for bavisant as a candidate for neuroprotective clinical trials in MS.