Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
Eur J Hum Genet. 2021 Sep;29(9):1369-1376. doi: 10.1038/s41431-021-00811-2. Epub 2021 Feb 9.
Duchenne muscular dystrophy (DMD) is an X-linked progressive muscle-wasting disorder that is caused by a lack of functional dystrophin, a cytoplasmic protein necessary for the structural integrity of muscle. As variants in the dystrophin gene lead to a disruption of the reading frame, pharmacological treatments have only limited efficacy; there is currently no effective therapy and consequently, a significant unmet clinical need for DMD. Recently, novel genetic approaches have shown real promise in treating DMD, with advancements in the efficacy and tropism of exon skipping and surrogate gene therapy. CRISPR-Cas9 has the potential to be a 'one-hit' curative treatment in the coming decade. The current limitations of gene editing, such as off-target effects and immunogenicity, are in fact partly constraints of the delivery method itself, and thus research focus has shifted to improving the viral vector. In order to halt the loss of ambulation, early diagnosis and treatment will be pivotal. In an era where genetic sequencing is increasingly utilised in the clinic, genetic therapies will play a progressively central role in DMD therapy. This review delineates the relative merits of cutting-edge genetic approaches, as well as the challenges that still need to be overcome before they become clinically viable.
杜氏肌营养不良症（DMD）是一种 X 连锁的进行性肌肉消耗性疾病，由功能性肌营养不良蛋白缺失引起，肌营养不良蛋白是维持肌肉结构完整性所必需的细胞质蛋白。由于肌营养不良蛋白基因的变异导致阅读框中断，药理学治疗的疗效有限；目前尚无有效的治疗方法，因此 DMD 存在显著的未满足的临床需求。最近，新型基因治疗方法在治疗 DMD 方面显示出了真正的前景，外显子跳跃和替代基因治疗的疗效和靶向性都有所提高。CRISPR-Cas9 在未来十年内有可能成为一种“一击即中”的治愈性治疗方法。基因编辑的当前限制，如脱靶效应和免疫原性，实际上部分是由于递送方法本身的限制，因此研究重点已转移到改善病毒载体。为了阻止行走能力的丧失，早期诊断和治疗将至关重要。在基因测序越来越多地应用于临床的时代，基因治疗将在 DMD 治疗中发挥越来越重要的作用。本文阐述了前沿基因治疗方法的相对优势，以及在这些方法变得具有临床可行性之前仍需克服的挑战。
