Neonatal gene therapy achieves sustained disease rescue of maple syrup urine disease in mice

Author:

Pontoizeau Clément,Simon-Sola Marcelo,Gaborit Clovis,Nguyen VincentORCID,Rotaru Irina,Tual Nolan,Colella PasqualinaORCID,Girard Muriel,Biferi Maria-Grazia,Arnoux Jean-Baptiste,Rötig AgnèsORCID,Ottolenghi Chris,de Lonlay Pascale,Mingozzi Federico,Cavazzana MarinaORCID,Schiff ManuelORCID

Abstract

AbstractMaple syrup urine disease (MSUD) is a rare recessively inherited metabolic disorder causing accumulation of branched chain amino acids leading to neonatal death, if untreated. 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. 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. We establish and characterize the Bckdha (branched chain keto acid dehydrogenase a)−/− mouse that exhibits a lethal neonatal phenotype mimicking human MSUD. Animals were treated at P0 with intravenous human BCKDHA AAV8 vectors under the control of either a ubiquitous or a liver-specific promoter. BCKDHA gene transfer rescued the lethal phenotype. 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. Here we show efficacy of gene therapy for MSUD demonstrating its potential for clinical translation.

Funder

DIM Ile de France, DIM Thérapie génique

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary

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