A high-throughput screen identifies a candidate molecule that promotes remyelination with significant translational potential (S50.003)

Objective: To test the remyelinating potential of a candidate selective estrogen reuptake modulator (SERM). Background: In multiple sclerosis (MS), remyelination of the effected axons represents a key therapeutic target to attempt to reverse MS-associated widespread demyelination and consequent progression of disability. Utilizing a novel high-throughput screening technique, binary indicant for myelination using micropillar arrays (BIMA), we previously identified several clusters of small molecules that enhance oligodendrocyte precursor cell (OPC) differentiation. SERMs represent one such cluster. Here, we sought to establish the remyelinating properties of one SERM, Bazedoxifene (BZA). BZA is particularly attractive because, when combined with conjugated estrogens, it is FDA-approved to treat menopausal symptoms. Design/Methods: We quantified the percentage of differentiation of oligodendrocyte precursor cells into mature oligodendrocytes in BZA- vs. vehicle-treated wild-type rat purified OPC cultures. We then quantified the extent of myelination by oligodendrocytes in BZA- vs. vehicle-treated co-cultures of oligodendrocytes and dorsal root ganglion neurons (DRGs). Next, we compared rates of remyelination in a lesional model (lysolecithin-induced corpus callosum demyelination) in oral gavage BZA- vs. vehicle-treated wild-type adult mice. Finally, we compared BZA- vs. vehicle-treated outcomes of human embryonic stem (ES) cell-derived purified OPC cultures. Results: BZA significantly enhanced OPC differentiation in in vitro and in vivo murine models. It significantly accelerated the kinetics of myelination and remyelination in in vitro and in vivo murine models. Finally, it significantly enhanced OPC differentiation in human ES-derived OPC cultures. Conclusions: Taken together, BZA represents a particularly potent and attractive SERM that could be mediating OPC differentiation and myelination effects, with significant translational potential. Study Supported by: National Multiple Sclerosis Society. Disclosure: Dr. Rankin has nothing to disclose. Dr. Shen has nothing to disclose. Dr. Mei has nothing to disclose. Dr. Desponts has received personal compensation for activities with Inception Sciences as an employee. Dr. Desponts holds stock and/or stock options in Inception Sciences. Dr. Lorrain has received personal compensation for activities with Inception. Dr. Green has received personal compensation for activities with Inception Sciences, Mylan Pharma, Medimmune, and Bionure. Dr. Green has received personal compensation for serving on the board of Inception Sciences. Dr. Green holds stock and/or stock options in Inception Sciences. Dr. Green has received research support from Inception Sciences, Biogen, and Novartis. Dr. Chan has received personal compensation for activities with Inception. Dr. Bove has nothing to disclose.