Namgoong John Hyun, Bertoni Carmen
Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA,
Degener Neurol Neuromuscul Dis. 2016 May 13;6:37-48. doi: 10.2147/DNND.S71808. eCollection 2016.
Duchenne muscular dystrophy (DMD) is an autosomal dominant, X-linked neuromuscular disorder caused by mutations in dystrophin, one of the largest genes known to date. Dystrophin gene mutations are generally transmitted from the mother to male offspring and can occur throughout the coding length of the gene. The majority of the methodologies aimed at treating the disorder have focused on restoring a shorter, although partially functional, dystrophin protein. The approach has the potential of converting a severe DMD phenotype into a milder form of the disease known as Becker muscular dystrophy. Others have focused on ameliorating the disease by targeting secondary pathologies such as inflammation or loss of regeneration. Of great potential is the development of strategies that are capable of restoring full-length dystrophin expression due to their ability to produce a normal, fully functional protein. Among these strategies, the use of read-through compounds (RTCs) that could be administered orally represents an ideal option. Gentamicin has been previously tested in clinical trials for DMD with limited or no success, and its use in the clinic has been dismissed due to issues of toxicity and lack of clear benefits to patients. More recently, new RTCs have been identified and tested in animal models for DMD. This review will focus on one of those RTCs known as ataluren that has now completed Phase III clinical studies for DMD and at providing an overview of the different stages that have led to its clinical development for the disease. The impact that this new drug may have on DMD and its future perspectives will also be described, with an emphasis on the importance of further assessing the clinical benefits of this molecule in patients as it becomes available on the market in different countries.
杜兴氏肌肉营养不良症（DMD）是一种常染色体显性、X连锁的神经肌肉疾病，由肌营养不良蛋白（dystrophin）突变引起，肌营养不良蛋白是迄今已知的最大基因之一。肌营养不良蛋白基因突变通常由母亲传给男性后代，且可发生在该基因的整个编码长度上。大多数旨在治疗该疾病的方法都集中在恢复一种较短但部分有功能的肌营养不良蛋白。这种方法有可能将严重的DMD表型转化为一种较温和的疾病形式，即贝克氏肌肉营养不良症。其他方法则集中在通过针对诸如炎症或再生丧失等继发性病变来改善疾病。由于能够产生正常、功能完全的蛋白质，能够恢复全长肌营养不良蛋白表达的策略具有巨大潜力。在这些策略中，使用可口服的通读化合物（RTCs）是一个理想选择。庆大霉素此前已在DMD的临床试验中进行测试，但效果有限或未取得成功，由于毒性问题以及对患者缺乏明确益处，其在临床上的使用已被摒弃。最近，新的RTCs已被鉴定并在DMD动物模型中进行测试。本综述将聚焦于其中一种名为阿他芦伦（ataluren）的RTCs，它现已完成针对DMD的III期临床研究，并概述导致其针对该疾病进行临床开发的不同阶段。还将描述这种新药可能对DMD产生的影响及其未来前景，重点强调随着该分子在不同国家上市，进一步评估其对患者临床益处的重要性。
