Université Grenoble Alpes, Inserm, U1216, Grenoble Institut des Neurosciences, 38000 Grenoble, France.
Laboratory for Integrative and Systems Physiology, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
Brain. 2020 Jun 1;143(6):1686-1696. doi: 10.1093/brain/awaa105.
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.
核编码线粒体基因的突变可导致广泛的疾病谱，其中 Leigh 综合征是婴儿期最常见的疾病。由于标准的腺相关病毒（AAV）载体在成年患者全身注射时向外周器官和中枢神经系统的转导能力有限，因此这种严重疾病尚无有效的治疗方法。在这里，我们使用穿透血脑屏障的 AAV-PHP.B 载体在 Leigh 综合征的 Ndufs4 敲除小鼠模型中重新恢复基因表达。在 1 个月大的敲除小鼠中静脉内递送 AAV.PHP.B-Ndufs4 载体可恢复包括中枢神经系统在内的多个器官中的线粒体复合物 I 活性。这种基因替换策略延长了寿命，挽救了代谢参数，提供了行为改善，并纠正了 Ndufs4 敲除小鼠的脑、视网膜和心脏的病理表型。这些结果有力地证明了针对多个器官的基因治疗策略可以挽救涉及中枢神经系统的致命神经代谢疾病。
