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

Authors :
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 de Lonlay
Federico Mingozzi
Marina Cavazzana
Manuel Schiff
CHU Necker - Enfants Malades [AP-HP]
Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163)
Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)
Approches génétiques intégrées et nouvelles thérapies pour les maladies rares (INTEGRARE)
Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Généthon
Généthon
Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151))
Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)
Centre de recherche en Myologie – U974 SU-INSERM
Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)
Institut de Myologie
Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)
Cappella, Marisa
Source :
Nature Communications, Nature Communications, 2022, 13 (1), pp.3278. ⟨10.1038/s41467-022-30880-w⟩
Publication Year :
2022
Publisher :
Springer Science and Business Media LLC, 2022.

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.

Details

ISSN :
20411723
Volume :
13
Database :
OpenAIRE
Journal :
Nature Communications
Accession number :
edsair.doi.dedup.....a0aef083f4f2dd69766a18c9c114142f