Characterizing the oxysterol, 20-hydroxycholesterol, as a mediator of remyelination in multiple sclerosis

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Multiple sclerosis (MS) is the most common neurological disease of young adulthood, affecting an estimated 1 million individuals in the U.S. and 2.5 million worldwide. MS is an autoimmune disease mediated by immune cells that trigger demyelination and neuronal damage of the central nervous system (CNS), resulting in debilitating neurological symptoms. While disease-modifying therapies have proven to be efficacious, they only prolong remission, they do not change disease course, and the majority of individuals with MS will likely experience worsening of clinical symptoms during the course of their disease. There is a significant gap in knowledge with respect to curative therapies for MS that prompt oligodendrocyte precursor cells to differentiate into mature oligodendrocytes (ODs), the main remyelinating cells within the adult CNS. Presented are exciting preliminary data in a white matter injury model of adult mice that establishes that 20-hydroxycholestrol (20HC) is capable of triggering remyelination in the CNS, and that it is capable of differentiating new ODs from the quiescent pool of OPCs in the CNS beyond the limited spontaneous regeneration that occurs during disease course. This resubmitted proposal builds upon this evocative preliminary data in an animal model of demyelination and proposes the application of leading edge molecular approaches to understanding the mechanisms of 20HC effect. The long-term goal of this proposal is to identify the efficacy of 20HC as a completely novel drug for reversing the progressive course of MS.