Multiple sclerosis (MS) is a complex, debilitating neural disorder associated with significant morbidity and mortality. Disease etiology is a result o unknown environmental and genetic factors, while disease pathology presents as inflammatory injury to the central nervous system (CNS) causing physical incapacity. This damage is a result of autoimmune-mediated destruction of oligodendrocytes causing demyelination. Prolonged demyelination leads to axonal damage occurring either in focal lesion sites and/or widespread throughout the CNS, depending on presentation of the disease. MS is treated with disease-modifying agents that target the immune system in an attempt to reduce the frequency of relapses and delay disease progression. These drugs have had limited success in improving patient outcomes and lack the unmet need to promote immediate remyelination. Identifying drugs that induce resident oligodendrocyte progenitor cell (OPC) mediated remyelination would provide patients a vital mechanism to halt disease progression and improve function. Using an innovative pluripotent stem cell-based high throughput screening platform we have discovered a class of FDA approved drugs that enhance remyelination in mouse models of MS. In this grant we will use in vivo and in vitro models to study the cellular and molecular effects of this class o drugs on mouse and human OPCs. These studies will provide the basis for potential translation of this drug, or modified derivatives, to clinical testing as a remyelinating therapeutic.
Multiple sclerosis is a devastating, irreversible and progressive disease that results from damage to the insulating coating (myelin) around nerves. Unfortunately, no effective therapeutic is currently available to promote repair of this myelin coating. We have identified a drug that enhances generation of cells that make this myelin coating and we propose to test the mechanism by which it functions.
|Hubler, Zita; Allimuthu, Dharmaraja; Bederman, Ilya et al. (2018) Accumulation of 8,9-unsaturated sterols drives oligodendrocyte formation and remyelination. Nature 560:372-376|
|Lager, Angela M; Corradin, Olivia G; Cregg, Jared M et al. (2018) Rapid functional genetics of the oligodendrocyte lineage using pluripotent stem cells. Nat Commun 9:3708|