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

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...

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Main Authors:	Pedro Silva-Pinheiro, Raffaele Cerutti, Marta Luna-Sanchez, Massimo Zeviani, Carlo Viscomi
Format:	Article
Language:	English
Published:	Elsevier 2020-06-01
Series:	Molecular Therapy: Methods & Clinical Development
Subjects:	mitochondrial diseases gene therapy AAV Ndufs4 complex I OXPHOS
Online Access:	http://www.sciencedirect.com/science/article/pii/S2329050120300863

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spelling	doaj-8df2cebf8cc74595af229759906059a82020-11-25T03:34:39ZengElsevierMolecular Therapy: Methods & Clinical Development2329-05012020-06-011710711078A Single Intravenous Injection of AAV-PHP.B-hNDUFS4 Ameliorates the Phenotype of Ndufs4−/− MicePedro Silva-Pinheiro0Raffaele Cerutti1Marta Luna-Sanchez2Massimo Zeviani3Carlo Viscomi4MRC/University of Cambridge Mitochondrial Biology Unit, Hills Road, Cambridge CB2 0XY, UKMRC/University of Cambridge Mitochondrial Biology Unit, Hills Road, Cambridge CB2 0XY, UKMRC/University of Cambridge Mitochondrial Biology Unit, Hills Road, Cambridge CB2 0XY, UKDepartment of Neurosciences, University of Padova, Via Giustiniani, 2, 35128 Padova, Italy; Venetian Institute of Molecular Medicine, Via Orus, 2, 35128 Padova, Italy; Corresponding author: Massimo Zeviani, MD, PhD, Venetian Institute of Molecular Medicine, Via Orus, 2, Padova 35128, Italy.Department of Biomedical Sciences, University of Padova, Via Ugo Bassi, 58/B, 35131 Padova, Italy; Corresponding author: Carlo Viscomi, PhD, Department of Biomedical Sciences, University of Padova, Via Ugo Bassi, 58/B, 35131 Padova, Italy.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.http://www.sciencedirect.com/science/article/pii/S2329050120300863mitochondrial diseasesgene therapyAAVNdufs4complex IOXPHOS
collection	DOAJ
language	English
format	Article
sources	DOAJ
author	Pedro Silva-Pinheiro Raffaele Cerutti Marta Luna-Sanchez Massimo Zeviani Carlo Viscomi
spellingShingle	Pedro Silva-Pinheiro Raffaele Cerutti Marta Luna-Sanchez Massimo Zeviani Carlo Viscomi A Single Intravenous Injection of AAV-PHP.B-hNDUFS4 Ameliorates the Phenotype of Ndufs4−/− Mice Molecular Therapy: Methods & Clinical Development mitochondrial diseases gene therapy AAV Ndufs4 complex I OXPHOS
author_facet	Pedro Silva-Pinheiro Raffaele Cerutti Marta Luna-Sanchez Massimo Zeviani Carlo Viscomi
author_sort	Pedro Silva-Pinheiro
title	A Single Intravenous Injection of AAV-PHP.B-hNDUFS4 Ameliorates the Phenotype of Ndufs4−/− Mice
title_short	A Single Intravenous Injection of AAV-PHP.B-hNDUFS4 Ameliorates the Phenotype of Ndufs4−/− Mice
title_full	A Single Intravenous Injection of AAV-PHP.B-hNDUFS4 Ameliorates the Phenotype of Ndufs4−/− Mice
title_fullStr	A Single Intravenous Injection of AAV-PHP.B-hNDUFS4 Ameliorates the Phenotype of Ndufs4−/− Mice
title_full_unstemmed	A Single Intravenous Injection of AAV-PHP.B-hNDUFS4 Ameliorates the Phenotype of Ndufs4−/− Mice
title_sort	single intravenous injection of aav-php.b-hndufs4 ameliorates the phenotype of ndufs4−/− mice
publisher	Elsevier
series	Molecular Therapy: Methods & Clinical Development
issn	2329-0501
publishDate	2020-06-01
description	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.
topic	mitochondrial diseases gene therapy AAV Ndufs4 complex I OXPHOS
url	http://www.sciencedirect.com/science/article/pii/S2329050120300863
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A Single Intravenous Injection of AAV-PHP.B-hNDUFS4 Ameliorates the Phenotype of Ndufs4−/− Mice

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