Abstract
Mitochondrial diseases are a heterogeneous group of disorders, stemming from mutations in nuclear or mitochondrial DNA that encode for mitochondrial proteins. These mutations primarily hinder oxidative phosphorylation (OXPHOS), and while they are multi-systemic disorders, mitochondrial diseases disproportionately affect tissues with higher energy demand, such as the brain and the heart. Approximately 1 in 5000 people worldwide suffer from mitochondrial diseases, for which no cures or highly effective treatments yet exist. To assess the ability of gene replacement to prevent disease progression, we subjected two different CNS-deficient mouse models (Ndufs3/complex I) or Cox10/complex IV conditional knockouts) to gene therapy. We used retro-orbitally injected AAV-PHP.eB to deliver the missing gene to the CNS of these mice. In both cases, we observed survival extension from 5-6 to more than 15 months, with no detectable disease phenotypes. Likewise, molecular and cellular phenotypes were mostly recovered in the treated mice. Surprisingly, these remarkable phenotypic improvements were achieved with only approximately 30% of neurons expressing the transgene from the AAVPHP.eB vector in the conditions used. These findings suggest that neurons lacking OXPHOS are protected by the surrounding neuronal environment and that partial compensation for neuronal OXPHOS loss can have disproportionately positive effects. This study offers a potential therapeutic approach to mitochondrial disease by early gene replacement therapy. Because of the species-specific limitations of AAV-PHP.eB, delivery to the human CNS remains a challenge.