Pharmacogenomic identification of small molecules promoting oligodendrogenesis and myelin repair

Multiple sclerosis (MS) is a chronic autoimmune-mediated disease characterized by focal demyelinated lesions of the central nervous system. Despite recent advances concentrated in stopping the immune attack towards oligodendrocytes in MS patients, efficient remyelinating therapies are still lacking. Remyelination occurs spontaneously in MS patients but it is inefficient and diminishes with aging and disease progression, leading to irreversible disability. Although some factors and small molecules have been shown to improve remyelination in cell culture as well as in remyelinating animal models, so far no medication presenting convincing remyelination capacity in humans has been approved for MS. Thus, enhancing remyelination remains an unmet medical need for MS patients. We recently identified key transcriptional networks and regulators involved in the specification of oligodendrocytes from neural stem cells (NSCs), as well as those mediating their maturation into myelinating cells based on the generation and expert curation of transcriptomic datasets generated by our labs and others' (bulk and single cell RNA-seq). We then performed a pharmacogenomics analysis to generate a list of novel small bioactive molecules regulating oligodendroglial-gene networks. Using neonatal mouse NSC and OPC cultures, we validated the ability of six of these molecules to foster oligodendrogenesis at different stages (proliferation or maturation). We then took advantage of an ex-vivo model of cerebellar slices explants, as well as expert advice of pharmacologists to select the two FDA-approved most promising molecules showing stronger or similar activity than positive controls thyroid hormone and clemastine. Interestingly, these two drugs have also reported anti-inflammatory activities. Combined with expertise from clinicians, we defined optimal posology and route of administration and characterized their activity in pre-clinicals study of adult mouse brain remyelination using the lysolecithin-induced focal demyelination model as well as in the model of neonatal hypoxia. Thus, we found a strong pro-oligodendrogenic activity in vivo, and we are currently assessing their potential impact on microglial and astroglial activation. Finally, this study will repurpose two novel FDA-approved drugs for clinical trials to assess their pro-remyelination activity in MS patients and preterm babies.