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.

中文翻译：

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恢复部分神经元有缺陷的氧化磷酸化可预防线粒体脑病。


氧化磷酸化 (OXPHOS) 缺陷可导致严重的脑病，并且这些疾病尚无有效的治疗方法。为了评估基因替换预防疾病进展的能力，我们对两种不同的 CNS 缺陷小鼠模型（Ndufs3/complex I 或 Cox10/complex IV 条件敲除）进行基因治疗。我们使用眼眶后注射 AAV-PHP.eB 将缺失的基因传递到这些小鼠的中枢神经系统。在这两种情况下，我们观察到生存期从 5-6 个月延长至 15 个月以上，且未检测到疾病表型。同样，在接受治疗的小鼠中，分子和细胞表型大部分得到恢复。令人惊讶的是，在所用条件下，仅约 30% 的神经元表达来自 AAV-PHP.eB 载体的转基因，就实现了这些显着的表型改善。这些发现表明，缺乏 OXPHOS 的神经元受到周围神经元环境的保护，并且对神经元 OXPHOS 损失的部分补偿可能会产生不成比例的积极影响。