Author Of 1 Presentation
LB1196 - Enhancing myelin repair in MS preclinical models by modulating the cholesterol biosynthesis pathway (ID 2021)
Abstract
Background
Enhancing remyelination in MS is the next frontier in therapeutic approaches to stop disease progression and improve neurological disabilities. However, an efficacious remyelination therapy is yet to be developed. One approach to enhance myelin repair which has been extensively demonstrated in response to a variety of stimuli, hinges on pharmacological stimulation of CNS resident oligodendrocyte progenitor cells (OPC), to mature into myelinating oligodendrocytes.
Objectives
Our goal is to develop an efficacious remyelination therapy to be administered conjunctive with existent immunomodulators.
Methods
In this pathway, we have determined a major role for the sterol isomerase Emopamil Binding Protein (EBP), which converts 8,9 into 7,8-unsaturated sterols, an essential step in cholesterol biosynthesis. Sterol accumulation can be measured by mass spectrometry in cultured OPCs and in CNS tissue from rodents treated with EBP inhibitors.
Results
Treatment of cultured OPCs with EBP inhibitors dramatically increased maturation as a consequence of elevated sterol accumulation. In vivo, we observed a robust accumulation of intermediate sterols in mouse brains within hours of peripheral administration of EBP inhibitors. Moreover, EBP inhibition significantly enhanced myelin repair after demyelination caused by focal injections of lysolecithin in the mouse spinal cord and in a chronic de/remyelination animal model.
Conclusions
Extensive preclinical validation supports EBP as viable target for a remyelination therapy in MS. Identification of novel, selective and safe small molecule inhibitors of EBP is undergoing with several advanced chemical series showing high efficacy in vitro and in pharmacodynamic assays.