Journal
BRAIN
Volume 143, Issue -, Pages 1686-1696Publisher
OXFORD UNIV PRESS
DOI: 10.1093/brain/awaa105
Keywords
gene therapy; neurometabolic disease; mitochondria; AAV vector
Categories
Funding
- Fondazione Telethon [TMMDMTX16TT]
- Agence Nationale de la Recherche (ANR-JCJC program) [ANR-17-CE37-0008-01]
- Agence Nationale de la Recherche [ANR-15-IDEX-02 NeuroCoG]
- European Research Council [ERC-AdG-787702, ERC.311682]
- Swiss National Science Foundation [SNSF 310030B-160318]
- Strategic Focal Area Personalized Health and Related Technologies (PHRT) of the ETH Domain [2018-422]
- GRL grant of the National Research Foundation of Korea [NRF GRL 2017K1A1A2013124]
- EPFL
- IDEX Chair of Excellence from the University of Grenoble-Alpes
- Edmond J. Safra Foundation
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Mutations in nuclear-encoded mitochondrial genes are responsible for a broad spectrum of disorders among which Leigh syndrome is the most common in infancy. No effective therapies are available for this severe disease mainly because of the limited capabilities of the standard adeno-associated viral (AAV) vectors to transduce both peripheral organs and the CNS when injected systemically in adults. Here, we used the brain-penetrating AAV-PHP.B vector to reinstate gene expression in the Ndufs4 knockout mouse model of Leigh syndrome. Intravenous delivery of an AAV.PHP.B-Ndufs4 vector in 1-month-old knockout mice restored mitochondrial complex I activity in several organs including the CNS. This gene replacement strategy extended lifespan, rescued metabolic parameters, provided behavioural improvement, and corrected the pathological phenotype in the brain, retina, and heart of Ndufs4 knockout mice. These results provide a robust proof that gene therapy strategies targeting multiple organs can rescue fatal neurometabolic disorders with CNS involvement.
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