Gene replacement therapy provides benefit in an adult mouse model of Leigh syndrome

Mutations in nuclear-encoded mitochondrial genes are responsible for a broad spectrum of disorders among which Leigh syndrome (LS) 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 central nervous system (CNS) when injected systemically in adults. Here, we used the brain-penetrating AAV-PHP.B vector to reinstate gene expression in the Ndufs4 KO mouse model of LS. Intravenous delivery of an AAV.PHP.B-Ndufs4 vector in 1-month old KO mice restored mitochondrial complex I activity in several organs including the CNS. This gene replacement strategy extended lifespan, rescued metabolic parameters, provided behavioral improvement, and corrected the pathological phenotype in the brain, retina, and heart of Ndufs4 KO mice. These results provide a robust proof that gene therapy strategies targeting multiple organs can rescue fatal neurometabolic disorders with CNS involvement.