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

中文翻译：

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基因替代疗法在利氏综合征成年小鼠模型中提供了益处。

核编码线粒体基因的突变是造成广泛疾病的原因，其中Leigh综合征是婴儿期最常见的疾病。对于这种严重疾病，目前尚无有效的治疗方法，主要是因为在成人体内全身注射标准腺相关病毒（AAV）载体转导周围器官和中枢神经系统的能力有限。在这里，我们使用了可穿透大脑的AAV-PHP.B载体恢复了Leigh综合征的Ndufs4基因敲除小鼠模型中的基因表达。静脉内递送AAV.PHP.B- Ndufs41个月大的基因敲除小鼠中的载体恢复了包括CNS在内的多个器官的线粒体复合体I活性。这种基因替代策略延长了寿命，挽救了代谢参数，改善了行为，并纠正了Ndufs4基因敲除小鼠的大脑，视网膜和心脏的病理表型。这些结果提供了有力的证据，证明针对多个器官的基因治疗策略可以挽救中枢神经系统参与的致命性神经代谢疾病。