LAUSR

Glutaric aciduria type I (GA-1) is an inborn error of metabolism with a severe neurological phenotype caused by the deficiency of glutaryl–coenzyme A dehydrogenase (GCDH), the last enzyme of lysine catabolism. Current literature suggests that toxic catabolites in the brain are produced locally and do not cross the blood-brain barrier. In a series of experiments using knockout mice of the lysine catabolic pathway and liver cell transplantation, we uncovered that toxic GA-1 catabolites in the brain originated from the liver. Moreover, the characteristic brain and lethal phenotype of the GA-1 mouse model was rescued by two different liver-directed gene therapy approaches: Using an adeno-associated virus, we replaced the defective Gcdh gene or we prevented flux through the lysine degradation pathway by CRISPR deletion of the aminoadipate-semialdehyde synthase (Aass) gene. Our findings question the current pathophysiological understanding of GA-1 and reveal a targeted therapy for this devastating disorder. Description Manipulation of lysine catabolism in the liver rescues glutaric aciduria and prevents metabolic and neuropathological phenotypes. A brain-liver toxic metabolite axis Glutaric aciduria type I (GA-1) stems from a genetic deficiency in lysine catabolism that results in the buildup of toxic catabolites throughout the body, including the brain, where they produce severe neurological symptoms. It is thought that toxic GA-1 neural catabolites originate locally within the brain; however, Barzi et al. show in a GA-1 mouse model that these catabolites originate from the liver and then cross the blood-brain barrier. Gene therapy approaches targeting liver metabolism were sufficient to arrest the accumulation of toxic catabolites in the brains of the GA-1 mice, improving both survival and neural phenotypes. —CAC