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AAV9-based gene therapy partially ameliorates the clinical phenotype of a mouse model of Leigh syndrome

Published version
Peer-reviewed

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Article

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Authors

Viscomi, CF 
Zeviani, M 

Abstract

Leigh syndrome (LS) is the most common infantile mitochondrial encephalopathy. No treatment is currently available for this condition. Mice lacking Ndufs4, encoding NADH: ubiquinone oxidoreductase iron-sulfur protein 4 recapitulates the main findings of complex I related LS, including severe multisystemic complex I deficiency and progressive neurodegeneration. In order to develop a gene therapy approach for LS, we used here an AAV2/9 vector carrying the human NDUFS4 coding sequence (hNDUFS4). We administered AAV2/9-hNDUFS4 by intravenous (IV) and/or intracerebroventricular (ICV) routes to either newborn or young Ndufs4/ mice. We found that IV administration alone was only able to correct the complex I deficiency in peripheral organs, while ICV administration partially corrected the deficiency in the brain. However, both treatments failed to improve the clinical phenotype or to prolong the lifespan of Ndufs4/ mice. In contrast, combined IV and ICV treatments resulted, along with increased complex I activity, in the amelioration of the rotarod performance, and in a significant prolongation of the lifespan. Our results indicate that extraneurological organs play an important role in LS pathogenesis, and provide an insight into current limitations of AAV-mediated gene therapy in multisystem disorders. These findings warrant future investigations to develop new vectors able to efficiently target multiple organs.

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Keywords

Mitochondrial disease, Leigh syndrome, AAV, gene therapy, Ndufs4, mouse models, experimental therapy

Journal Title

Gene Therapy

Conference Name

Journal ISSN

0969-7128
1476-5462

Volume Title

Publisher

Springer Nature
Sponsorship
European Research Council (322424)
Medical Research Council (MC_UP_1002/1)
Medical Research Council (MC_UU_00015/8)
MRC (MC_UU_00015/8)
Medical Research Council (MC_UU_00015/7)
This work was supported by the Core Grant from the MRC, ERC advanced grant FP7- 322424 and NRJ-Institut de France Grant (to MZ) and by the grant [GR-2010-2306- 756] from the Italian Ministry of Health (to CV).