Center for Gene Therapy, Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, Ohio, USA.
Departments of Pediatrics and Neurology, Ohio State University Wexner Medical Center, Columbus, Ohio, USA.
Pediatr Pulmonol. 2021 Apr;56(4):710-720. doi: 10.1002/ppul.25055. Epub 2020 Sep 14.
Both 5q-linked spinal muscular atrophy (SMA) and Duchenne muscular dystrophy (DMD) are fatal monogenic neuromuscular disorders caused by loss-of-function mutations. SMA is an autosomal recessive disorder affecting motor neurons that is typically caused by homozygous whole-gene deletions of SMN1. DMD is an X-linked recessive muscle disease most often due to exon deletions, but also duplications and smaller sized variants within the DMD gene. Gene replacement therapy offers the opportunity to correct the underlying genetic defect by the introduction of a functional gene. We review the transformative work from clinical trials to United States Food and Drug Administration approval of onasemnogene abeparvovec-xioi in SMA and its application in clinical practice and the early results of microdystrophin delivery in DMD. We also review the introduction of antisense oligonucleotides to alter pre-messenger RNA splicing to promote exon inclusion (as in nusinersen in SMA) or exclusion (as in eteplirsen in DMD) into neuromuscular therapeutics. There are multiple promising novel genetically mediated therapies on the horizon, which in aggregate point towards a hopeful future for individuals with SMA and DMD.
5q 连接型脊髓性肌萎缩症（SMA）和杜氏肌营养不良症（DMD）都是致命的单基因神经肌肉疾病，由功能丧失突变引起。SMA 是一种常染色体隐性遗传病，影响运动神经元，通常由 SMN1 基因的纯合全基因缺失引起。DMD 是一种 X 连锁隐性肌肉疾病，最常见的原因是外显子缺失，但也有 DMD 基因内的重复和较小的变体。基因替代疗法通过引入功能性基因提供了纠正潜在遗传缺陷的机会。我们回顾了从临床试验到美国食品和药物管理局批准 SMA onasemnogene abeparvovec-xioi 及其在临床实践中的应用，以及 DMD 中小 dystrophin 传递的早期结果。我们还回顾了引入反义寡核苷酸来改变前信使 RNA 剪接以促进外显子包含（如 SMA 中的 nusinersen）或排除（如 DMD 中的 eteplirsen）进入神经肌肉治疗的情况。有多种有前途的新型基因介导疗法即将出现，这些疗法总体上为 SMA 和 DMD 患者带来了充满希望的未来。
