Department of Medical Genetics, University of Alberta Faculty of Medicine and Dentistry, Edmonton Canada.
Muscular Dystrophy Canada Research Chair, Edmonton Canada.
Expert Rev Mol Med. 2019 Oct 2;21:e5. doi: 10.1017/erm.2019.5.
Muscular dystrophy is a group of genetic disorders characterised by degeneration of muscles. Different forms of muscular dystrophy can show varying phenotypes with a wide range of age, severity and location of muscle deterioration. Many palliative care options are available for muscular dystrophy patients, but no curative treatment is available. Exon-skipping therapy aims to induce skipping of exons with disease-causing mutations and/or nearby exons to restore the reading frame, which results in an internally truncated, partially functional protein. In antisense-mediated exon-skipping synthetic antisense oligonucleotide binds to pre-mRNA to induce exon skipping. Recent advances in exon skipping have yielded promising results; the US Food and Drug Administration (FDA) approved eteplirsen (Exondys51) as the first exon-skipping drug for the treatment of Duchenne muscular dystrophy, and in vivo exon skipping has been demonstrated in animal models of dysferlinopathy, limb-girdle muscular dystrophy type 2C and congenital muscular dystrophy type 1A. Novel methods that induce exon skipping utilizing Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) are also being developed where splice site mutations are created within the genome to induce exon skipping. Challenges remain as exon-skipping agents can have deleterious non-specific effects and different in-frame deletions show phenotypic variance. This article reviews the state of the art of exon skipping for treating muscular dystrophy and discusses challenges and future prospects.
肌肉萎缩症是一组以肌肉退化为特征的遗传疾病。不同形式的肌肉萎缩症可能表现出不同的表型，其发病年龄、严重程度和肌肉恶化部位差异较大。肌肉萎缩症患者有许多姑息治疗选择，但目前尚无治愈方法。外显子跳跃疗法旨在诱导致病突变和/或附近外显子的跳跃，以恢复阅读框，从而产生内部截断、部分功能的蛋白质。在反义介导的外显子跳跃中，合成反义寡核苷酸与前体 mRNA 结合以诱导外显子跳跃。外显子跳跃的最新进展取得了可喜的成果；美国食品和药物管理局 (FDA) 批准了 eteplirsen (Exondys51) 作为治疗杜氏肌营养不良症的第一种外显子跳跃药物，并且在肌营养不良症、肢带型肌营养不良症 2C 和先天性肌肉萎缩症 1A 的动物模型中已经证明了体内外显子跳跃。利用规律成簇间隔短回文重复 (CRISPR) 诱导外显子跳跃的新方法也正在开发中，其中在基因组内创建剪接位点突变以诱导外显子跳跃。外显子跳跃剂可能具有有害的非特异性作用，不同的框内缺失表现出表型差异，这仍然是一个挑战。本文综述了用于治疗肌肉萎缩症的外显子跳跃的最新进展，并讨论了挑战和未来前景。
