Restoration of defective oxidative phosphorylation to a subset of neurons prevents mitochondrial encephalopathy

Oxidative Phosphorylation (OXPHOS) defects can cause severe encephalopathies and no effective treatment exists for these disorders. 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 ~30% of neurons expressing the transgene from the AAV-PHP.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. Synopsis Mitochondrial diseases are often caused by mutations in nuclear genes, affecting predominantly the CNS. Early intervention with AAV-PHP.eB-driven gene replacement successfully prevented the onset of encephalopathy in neuronal-knockouts of critical oxidative phosphorylation genes (Ndufs3 or Cox10). Pre-symptomatic administration of AAV-PHP.eB-driven gene replacement prevented onset of encephalopathic phenotype and extended lifespan. Gene replacement therapy decreased neuroinflammation. A transfection rate of 30% of neurons was sufficient to prevent disease onset. Mitochondrial diseases are often caused by mutations in nuclear genes, affecting predominantly the CNS. Early intervention with AAV-PHP.eB-driven gene replacement successfully prevented the onset of encephalopathy in neuronal-knockouts of critical oxidative phosphorylation genes (Ndufs3 or Cox10).