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

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Viscomi, CF 
Zeviani, M 


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.



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

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Gene Therapy

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Springer Nature
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).