Pantothenate kinase activation restores brain coenzyme A in a mouse model of pantothenate kinase associated neurodegeneration .

Pantothenate kinase associated neurodegeneration (PKAN) is characterized by a motor disorder with combinations of dystonia, parkinsonism and spasticity, leading to premature death. PKAN is caused by mutations in the PANK2 gene that result in loss or reduction of PANK2 protein function. PANK2 is one of three kinases that initiate and regulate coenzyme A biosynthesis from vitamin B5 and the ability of BBP-671, an allosteric activator of pantothenate kinases, to enter the brain and elevate coenzyme A was investigated. The metabolic stability, protein binding and membrane permeability of BBP-671 all suggest it has the physical properties required to cross the blood brain barrier. BBP-671 was detected in plasma, liver, cerebrospinal fluid and brain following oral administration in rodents demonstrating the ability of BBP-671 to penetrate the brain. The pharmacokinetic and pharmacodynamic properties of orally administered BBP-671 evaluated in cannulated rats showed that CoA concentrations were elevated in blood, liver and brain. BBP-671 elevation of whole blood acetyl-CoA served as a peripheral pharmacodynamic marker and provided a suitable method to assess target engagement. BBP-671 treatment elevated brain coenzyme A concentrations, and improved movement and body weight in a PKAN mouse model. Thus, BBP-671 crosses the blood brain barrier to correct the brain CoA deficiency in a PKAN mouse model resulting in improved locomotion and survival, providing a preclinical foundation for the development of BBP-671 as a potential treatment for PKAN. Significance Statement The blood brain barrier represents a major hurdle for drugs targeting brain metabolism. This work describes the pharmacokinetic/pharmacodynamic properties of BBP-671, a pantothenate kinase activator. BBP-671 crosses the blood brain barrier to correct the neuron-specific CoA deficiency and improve motor function in a mouse model of pantothenate kinase associated neurodegeneration. The central role of CoA and acetyl-CoA in intermediary metabolism suggests that pantothenate kinase activators may be useful in modifying neurological metabolic disorders.