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Duke University Team Identifies Liver as Source of Toxic Catabolites in Rare Inherited Disease

Through a series of transplant experiments, a team led by scientist from Duke University has uncovered the source of toxic catabolites that cause the rare metabolic disorder glutaric aciduria type I (GA-1), pointing to potential new therapeutic approaches for the inherited disease. GA-1 is caused by a deficiency of the mitochondrial enzyme glutaryl-CoA dehydrogenase, the last enzyme of lysine catabolism, and frequently leads to severe long-term neurological disabilities. It is widely accepted that the toxic catabolites that build up in the brains of GA-1 patients are locally produced and do not cross the blood-brain barrier, and current treatments focus on substate reduction. Given that toxic catabolites originating from the liver can accumulate in the brain in other amino acid disorders, the researchers performed experiments in knockout mice to investigate the origin of toxic metabolites in GA-1, showing that they do in fact originate in the liver. Importantly, the scientists were able to rescue the lethal brain phenotype of a GA-1 mouse model using two different liver-directed gene therapy approaches. The findings, appearing in Science Translational Medicine this week, challenge the current dogma that the toxic catabolites in GA-1 originate in the brain and indicate that the liver could be targeted with new therapies for the disease.