Center for Integrative Brain Research, Seattle Children's Reserach Institute, Seattle, WA, 98101, USA.
Papé Family Pediatric Research Institute, Oregon Health and Science University, Portland, OR, 97239, USA.
Orphanet J Rare Dis. 2022 Jun 6;17(1):217. doi: 10.1186/s13023-022-02324-7.
Mitochondrial diseases are a group of rare, heterogeneous diseases caused by gene mutations in both nuclear and mitochondrial genomes that result in defects in mitochondrial function. They are responsible for significant morbidity and mortality as they affect multiple organ systems and particularly those with high energy-utilizing tissues, such as the nervous system, skeletal muscle, and cardiac muscle. Virtually no effective treatments exist for these patients, despite the urgent need. As the majority of these conditions are monogenic and caused by mutations in nuclear genes, gene replacement is a highly attractive therapeutic strategy. Adeno-associated virus (AAV) is a well-characterized gene replacement vector, and its safety profile and ability to transduce quiescent cells nominates it as a potential gene therapy vehicle for several mitochondrial diseases. Indeed, AAV vector-based gene replacement is currently being explored in clinical trials for one mitochondrial disease (Leber hereditary optic neuropathy) and preclinical studies have been published investigating this strategy in other mitochondrial diseases. This review summarizes the preclinical findings of AAV vector-based gene replacement therapy for mitochondrial diseases including Leigh syndrome, Barth syndrome, ethylmalonic encephalopathy, and others.
线粒体疾病是一组由核基因组和线粒体基因组中的基因突变引起的罕见、异质性疾病，导致线粒体功能缺陷。它们会影响多个器官系统，特别是那些需要高能量利用组织的系统，如神经系统、骨骼肌和心肌，因此导致很高的发病率和死亡率。尽管有迫切的需求，但实际上针对这些患者还没有有效的治疗方法。由于这些疾病大多数是单基因疾病，由核基因突变引起，因此基因替代是一种极具吸引力的治疗策略。腺相关病毒 (AAV) 是一种特征明确的基因替代载体，其安全性和对静息细胞的转导能力使其成为几种线粒体疾病的潜在基因治疗载体。事实上，基于 AAV 载体的基因替代目前正在针对一种线粒体疾病（莱伯遗传性视神经病变）进行临床试验，并且已经发表了关于该策略在其他线粒体疾病中的研究的临床前研究。本综述总结了基于 AAV 载体的基因替代治疗线粒体疾病的临床前研究结果，包括 Leigh 综合征、Barth 综合征、乙基丙二酸脑病等。
