Wells Dominic J
Gene Targeting Group, Department of Cellular and Molecular Neuroscience, Division of Neuroscience and Mental Health, Imperial College London, Charing Cross Hospital, London, W6 8RP, UK.
J Muscle Res Cell Motil. 2006;27(5-7):387-98. doi: 10.1007/s10974-006-9081-6. Epub 2006 Jul 28.
It is 20 years since the discovery of the genetic defect causing Duchenne muscular dystrophy (DMD). This X-linked progressive and fatal myopathy is due to the absence of a functional version of a critical sub-sarcolemmal protein called dystrophin that appears to act both as a structural and as a signalling molecule in the muscle fibre. A number of molecular approaches have been developed to restore the expression of dystrophin in DMD patients. Pre-clinical experiments have demonstrated the potential of delivery of recombinant versions of the DMD gene using viral or non-viral vectors and importantly several of these systems are compatible with vascular delivery, an essential feature as all muscles are affected in this condition. Other studies have shown that antisense oligonucleotides can modify the splicing of the primary transcript to provide an internally truncated but still functional protein. Alternatively, in approximately 10-20% of cases it is possible to chemically persuade the translational machinery to read-through a pre-mature stop codon. The pre-clinical results of the last 4 years have encouraged the development of clinical trials for all of the above.
自发现导致杜氏肌营养不良症（DMD）的基因缺陷以来已有20年。这种X连锁的进行性致命性肌病是由于缺乏一种关键的肌膜下蛋白——抗肌萎缩蛋白的功能性版本，该蛋白在肌纤维中似乎既起结构分子作用又起信号分子作用。已经开发了多种分子方法来恢复DMD患者抗肌萎缩蛋白的表达。临床前实验已经证明了使用病毒或非病毒载体递送DMD基因重组版本的潜力，重要的是这些系统中的几种与血管递送兼容，这是一个基本特征，因为在这种情况下所有肌肉都会受到影响。其他研究表明，反义寡核苷酸可以修饰初级转录本的剪接，以提供一种内部截短但仍具功能的蛋白质。或者，在大约10% - 20%的病例中，可以通过化学方法促使翻译机制通读提前出现的终止密码子。过去4年的临床前结果推动了上述所有方法的临床试验发展。
