A Selective PanK3 Activator Restores Coenzyme A in Cellular and Mouse Models of Pantothenate Kinase-Associated Neurodegeneration.

Pantothenate kinase-associated neurodegeneration, PKAN, is a rare progressive neurodegenerative disorder associated with iron accumulation in the brain. The disease, which causes early immobility and often death by early adulthood, is caused by loss of function mutations in the human PANK2 gene, encoding a key enzyme in the biosynthesis of coenzyme A from pantothenic acid. To date, no disease-modifying therapy exists for PKAN, and current interventions are largely limited to symptomatic management. Herein we report the identification of a new class of direct activators of human PANK3, termed VTACs, designed to compensate for the loss of PANK2 function. Using cell and animal models of PanK2 deficiency, we demonstrate that a lead VTAC compound, VTAC-2, restores CoA levels to wild-type levels both in cells and in mouse brain. Moreover, the favorable physicochemical properties and oral bioavailability of VTAC-2 make this compound an attractive candidate for clinical evaluation for the treatment of PKAN.