A Single Intravenous Injection of AAV-PHP.B-hNDUFS4 Ameliorates the Phenotype of Ndufs4 -/- Mice.

Abstract

Leigh syndrome, or infantile necrotizing subacute encephalopathy (OMIM #256000), is one of the most common manifestations of mitochondrial dysfunction, due to mutations in more than 75 genes, with mutations in respiratory complex I subunits being the most common cause. In the present study, we used the recently described PHP.B serotype, characterized by efficient capacity to cross the blood-brain barrier, to express the hNDUFS4 gene in the Ndufs4 -/- mouse model of Leigh disease. A single intravenous injection of PHP.B-hNDUFS4 in adult Ndufs4 -/- mice led to a normalization of the body weight, marked amelioration of the rotarod performance, delayed onset of neurodegeneration, and prolongation of the lifespan up to 1 year of age. hNDUFS4 protein was expressed in virtually all brain regions, leading to a partial recovery of complex I activity. Our findings strongly support the feasibility and effectiveness of adeno-associated viral vector (AAV)-mediated gene therapy for mitochondrial disease, particularly with new serotypes showing increased permeability to the blood-brain barrier in order to achieve widespread expression in the central nervous system.

• Authors: Pedro Silva-Pinheiro, Raffaele Cerutti, Marta Luna-Sanchez, Massimo Zeviani, Carlo Viscomi
• Journal: Molecular therapy. Methods & clinical development (Mol Ther Methods Clin Dev) Vol. 17 Pg. 1071-1078 (Jun 12 2020) ISSN: 2329-0501 [Print] United States
• PMID: 32478122 (Publication Type: Journal Article)
• Copyright: © 2020 The Authors.