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

Clément Pontoizeau (), Marcelo Simon-Sola, Clovis Gaborit, Vincent Nguyen, Irina Rotaru, Nolan Tual, Pasqualina Colella, Muriel Girard, Maria-Grazia Biferi, Jean-Baptiste Arnoux, Agnès Rötig, Chris Ottolenghi, Pascale Lonlay, Federico Mingozzi, Marina Cavazzana and Manuel Schiff ()
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Clément Pontoizeau: Paris Cité University
Marcelo Simon-Sola: Inserm UMR_S1163, Institut Imagine
Clovis Gaborit: Inserm UMR_S1163, Institut Imagine
Vincent Nguyen: Inserm UMR_S1163, Institut Imagine
Irina Rotaru: Inserm UMR_S1163, Institut Imagine
Nolan Tual: Inserm UMR_S1163, Institut Imagine
Pasqualina Colella: Généthon INTEGRARE UMR-S951, University of Evry
Muriel Girard: Paris Cité University
Maria-Grazia Biferi: Sorbonne University, Inserm, Institute of Myology, Centre of Research in Myology
Jean-Baptiste Arnoux: Paris Cité University
Agnès Rötig: Inserm UMR_S1163, Institut Imagine
Chris Ottolenghi: Paris Cité University
Pascale Lonlay: Paris Cité University
Federico Mingozzi: Généthon INTEGRARE UMR-S951, University of Evry
Marina Cavazzana: Inserm UMR_S1163, Institut Imagine
Manuel Schiff: Paris Cité University

Nature Communications, 2022, vol. 13, issue 1, 1-13

Abstract: Abstract 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. 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.

Date: 2022
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DOI: 10.1038/s41467-022-30880-w

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