![]() ![]() ![]() Maple syrup urine disease (MSUD, MIM: 248600) is one of the earliest described metabolic disorders. Monogenic inborn errors of metabolism are relevant targets for gene therapy as they are autosomal recessive conditions with well-characterized pathophysiology and highly informative biochemical readouts yet their therapeutic management remains complex and cumbersome. ![]() Here we show efficacy of gene therapy for MSUD demonstrating its potential for clinical translation. While the use of a ubiquitous promoter fully and sustainably rescued the disease (long-term survival, normal phenotype and correction of biochemical abnormalities), liver-specific expression of BCKDHA led to partial, though sustained rescue. BCKDHA gene transfer rescued the lethal phenotype. Animals were treated at P0 with intravenous human BCKDHA AAV8 vectors under the control of either a ubiquitous or a liver-specific promoter. We establish and characterize the Bckdha ( branched chain keto acid dehydrogenase a) −/− mouse that exhibits a lethal neonatal phenotype mimicking human MSUD. Here, based on significant liver contribution to the catabolism of the branched chain amino acid leucine, we develop a liver-directed adeno-associated virus (AAV8) gene therapy for MSUD. Treatment for MSUD represents an unmet need because the current treatment with life-long low-protein diet is challenging to maintain, and despite treatment the risk of acute decompensations and neuropsychiatric symptoms remains. Maple syrup urine disease (MSUD) is a rare recessively inherited metabolic disorder causing accumulation of branched chain amino acids leading to neonatal death, if untreated. ![]()
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