Lim Kenji Rowel Q, Maruyama Rika, Yokota Toshifumi
Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta.
Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta; The Friends of Garrett Cumming Research & Muscular Dystrophy Canada, HM Toupin Neurological Science Research Chair, Edmonton, AB, Canada.
Drug Des Devel Ther. 2017 Feb 28;11:533-545. doi: 10.2147/DDDT.S97635. eCollection 2017.
Duchenne muscular dystrophy is a fatal neuromuscular disorder affecting around one in 3,500-5,000 male births that is characterized by progressive muscular deterioration. It is inherited in an X-linked recessive fashion and is caused by loss-of-function mutations in the gene coding for dystrophin, a cytoskeletal protein that stabilizes the plasma membrane of muscle fibers. In September 2016, the US Food and Drug Administration granted accelerated approval for eteplirsen (or Exondys 51), a drug that acts to promote dystrophin production by restoring the translational reading frame of through specific skipping of exon 51 in defective gene variants. Eteplirsen is applicable for approximately 14% of patients with mutations. This article extensively reviews and discusses the available information on eteplirsen to date, focusing on pharmacological, efficacy, safety, and tolerability data from preclinical and clinical trials. Issues faced by eteplirsen, particularly those relating to its efficacy, will be identified. Finally, the place of eteplirsen and exon skipping as a general therapeutic strategy in Duchenne muscular dystrophy treatment will be discussed.
杜氏肌营养不良症是一种致命的神经肌肉疾病，在每3500至5000名男性新生儿中约有1人患病，其特征是进行性肌肉退化。它以X连锁隐性方式遗传，由编码抗肌萎缩蛋白的基因突变导致功能丧失引起，抗肌萎缩蛋白是一种细胞骨架蛋白，可稳定肌肉纤维的质膜。2016年9月，美国食品药品监督管理局加速批准了依特普伦（或Exondys 51），该药物通过在缺陷基因变体中特异性跳过外显子51来恢复的翻译阅读框，从而促进抗肌萎缩蛋白的产生。依特普伦适用于约14%的基因突变患者。本文广泛回顾和讨论了迄今为止有关依特普伦的现有信息，重点关注临床前和临床试验的药理学、疗效、安全性和耐受性数据。将确定依特普伦面临的问题，特别是与其疗效相关的问题。最后，将讨论依特普伦和外显子跳跃作为杜氏肌营养不良症治疗的一般治疗策略的地位。
