Primary mitochondrial diseases represent some of the most common and severe inherited metabolic disorders, affecting ~1 in 4,300 live births. The clinical and molecular diversity typified by mitochondrial diseases has contributed to the lack of licensed disease‐modifying therapies available. Management for the majority of patients is primarily supportive. The failure of clinical trials in mitochondrial diseases partly relates to the inefficacy of the compounds studied. However, it is also likely to be a consequence of the significant challenges faced by clinicians and researchers when designing trials for these disorders, which have historically been hampered by a lack of natural history data, biomarkers and outcome measures to detect a treatment effect. Encouragingly, over the past decade there have been significant advances in therapy development for mitochondrial diseases, with many small molecules now transitioning from preclinical to early phase human interventional studies. In this review, we present the treatments and management strategies currently available to people with mitochondrial disease. We evaluate the challenges and potential solutions to trial design and highlight the emerging pharmacological and genetic strategies that are moving from the laboratory to clinical trials for this group of disorders.

中文翻译：

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迈向线粒体疾病的临床试验

原发性线粒体疾病代表了一些最常见和最严重的遗传性代谢紊乱，每 4,300 名活产婴儿中约有 1 人受到影响。以线粒体疾病为代表的临床和分子多样性导致缺乏获得许可的疾病修饰疗法。大多数患者的治疗主要是支持性的。线粒体疾病临床试验的失败部分与所研究化合物的无效性有关。然而，这也可能是临床医生和研究人员在设计针对这些疾病的试验时面临的重大挑战的结果，这些试验历来因缺乏自然病程数据、生物标志物和检测治疗效果的结果指标而受到阻碍。令人鼓舞的是，在过去的十年里，线粒体疾病的治疗发展取得了重大进展，许多小分子现在从临床前研究过渡到早期人类干预研究。在这篇综述中，我们介绍了目前可用于线粒体疾病患者的治疗和管理策略。我们评估了试验设计的挑战和潜在的解决方案，并强调了正在从实验室转移到针对这组疾病的临床试验的新兴药理学和遗传策略。