Perkins Kelly J, Davies Kay E
Sir William Dunn School of Pathology.
MRC Functional Genomics Unit, University of Oxford, Oxford, UK,
Degener Neurol Neuromuscul Dis. 2012 Oct 11;2:141-164. doi: 10.2147/DNND.S26637. eCollection 2012.
Duchenne muscular dystrophy (DMD), an allelic X-linked progressive muscle-wasting disease, is one of the most common single-gene disorders in the developed world. Despite knowledge of the underlying genetic causation and resultant pathophysiology from lack of dystrophin protein at the muscle sarcolemma, clinical intervention is currently restricted to symptom management. In recent years, however, unprecedented advances in strategies devised to correct the primary defect through gene- and cell-based therapeutics hold particular promise for treating dystrophic muscle. Conventional gene replacement and endogenous modification strategies have greatly benefited from continued improvements in encapsidation capacity, transduction efficiency, and systemic delivery. In particular, RNA-based modifying approaches such as exon skipping enable expression of a shorter but functional dystrophin protein and rapid progress toward clinical application. Emerging combined gene- and cell-therapy strategies also illustrate particular promise in enabling ex vivo genetic correction and autologous transplantation to circumvent a number of immune challenges. These approaches are complemented by a vast array of pharmacological approaches, in particular the successful identification of molecules that enable functional replacement or ameliorate secondary DMD pathology. Animal models have been instrumental in providing proof of principle for many of these strategies, leading to several recent trials that have investigated their efficacy in DMD patients. Although none has reached the point of clinical use, rapid improvements in experimental technology and design draw this goal ever closer. Here, we review therapeutic approaches to DMD, with particular emphasis on recent progress in strategic development, preclinical evaluation and establishment of clinical efficacy. Further, we discuss the numerous challenges faced and synergistic approaches being devised to combat dystrophic pathology effectively.
杜兴氏肌营养不良症（DMD）是一种等位基因X连锁的进行性肌肉萎缩疾病，是发达国家最常见的单基因疾病之一。尽管已知潜在的遗传病因以及由于肌膜上缺乏抗肌萎缩蛋白而导致的病理生理学，但目前临床干预仅限于症状管理。然而，近年来，通过基于基因和细胞的疗法来纠正原发性缺陷的策略取得了前所未有的进展，这为治疗营养不良性肌肉带来了特别的希望。传统的基因替代和内源性修饰策略因衣壳化能力、转导效率和全身递送方面的持续改进而受益匪浅。特别是，基于RNA的修饰方法，如外显子跳跃，能够表达较短但有功能的抗肌萎缩蛋白，并在临床应用方面取得了快速进展。新兴的基因和细胞联合治疗策略在实现体外基因校正和自体移植以规避一些免疫挑战方面也显示出特别的前景。这些方法得到了大量药理学方法补充，特别是成功鉴定出能够实现功能替代或改善继发性DMD病理的分子。动物模型有助于为许多这些策略提供原理证明，从而促成了最近几项研究它们在DMD患者中疗效的试验。尽管目前尚无一种方法达到临床应用阶段，但实验技术和设计的快速改进使这一目标越来越近。在此，我们综述了DMD的治疗方法，特别强调了战略发展、临床前评估和临床疗效确立方面的最新进展。此外，我们讨论了所面临的众多挑战以及为有效对抗营养不良性病理而设计的协同方法。
