The landscape of targets and lead molecules for remyelination

Remyelination, or the restoration of myelin sheaths around axons in the central nervous system, is a multi-stage repair process that remains a major need for millions of patients with multiple sclerosis and other diseases of myelin. Even into adulthood, rodents and humans can generate new myelin-producing oligodendrocytes, leading to the therapeutic hypothesis that enhancing remyelination could lessen disease burden in multiple sclerosis. Multiple labs have used phenotypic screening to identify dozens of drugs that enhance oligodendrocyte formation, and several hit molecules have now advanced to clinical evaluation. Target identification studies have revealed that a large majority of these hits share the ability to inhibit a narrow range of cholesterol pathway enzymes and thereby induce cellular accumulation of specific sterol precursors to cholesterol. This Perspective surveys the recent fruitful intersection of chemical biology and remyelination and suggests multiple approaches toward new targets and lead molecules to promote remyelination.