Relief of CoA sequestration and restoration of mitochondrial function in a mouse model of propionic acidemia

Propionic acidemia (PA, OMIM 606054) is a devastating inborn error of metabolism arising from mutations that reduce the activity of the mitochondrial enzyme propionyl‐CoA carboxylase (PCC). The defects in PCC reduce the concentrations of nonesterified coenzyme A (CoASH), thus compromising mitochondrial function and disrupting intermediary metabolism. Here, we use a hypomorphic PA mouse model to test the effectiveness of BBP‐671 in correcting the metabolic imbalances in PA. BBP‐671 is a high‐affinity allosteric pantothenate kinase activator that counteracts feedback inhibition of the enzyme to increase the intracellular concentration of CoA. Liver CoASH and acetyl‐CoA are depressed in PA mice and BBP‐671 treatment normalizes the cellular concentrations of these two key cofactors. Hepatic propionyl‐CoA is also reduced by BBP‐671 leading to an improved intracellular C3:C2‐CoA ratio. Elevated plasma C3:C2‐carnitine ratio and methylcitrate, hallmark biomarkers of PA, are significantly reduced by BBP‐671. The large elevations of malate and α‐ketoglutarate in the urine of PA mice are biomarkers for compromised tricarboxylic acid cycle activity and BBP‐671 therapy reduces the amounts of both metabolites. Furthermore, the low survival of PA mice is restored to normal by BBP‐671. These data show that BBP‐671 relieves CoA sequestration, improves mitochondrial function, reduces plasma PA biomarkers, and extends the lifespan of PA mice, providing the preclinical foundation for the therapeutic potential of BBP‐671.