Systemic Delivery of AAV- Mitigates the Phenotypes of Mitochondrial Disorders in Mutant Mice.

Gene therapy now provides a novel approach for treating inherited monogenetic disorders, including nuclear gene mutations associated with mitochondrial diseases. In this study, we have utilized a mouse model carrying a p.Arg389Gln mutation of the mitochondrial gene () and treated them with neurotropic AAV-PHP.B vector loaded with the mouse cDNA sequence. We then used immunofluorescence staining and western blot to test the transduction efficiency of this vector. Toluidine blue staining and electronic microscopy were also utilized to assess the morphology of optic and sciatic nerves, and the mitochondrial respiratory chain activity was determined as well. The AAV vector effectively transduced in the central nervous system and peripheral organs, and AAV- treatment reversed almost all the symptoms of the mutants ( This therapy also improved the electronic conductivity of the sciatic nerves, prevented optic atrophy, improved mobility, and restored mitochondrial complex function. Most notably, the sensory neuropathy, neurodegeneration, and chronic neuroinflammation in the brain were alleviated. Overall, we present the first demonstration of a potential definitive treatment that significantly improves optic and sciatic nerve atrophy, sensory neuropathy, and mitochondrial dysfunction in related mitochondriopathy. Our study provides substantial support for the translation of AAV-based gene therapy into clinical applications.