Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3QX, UK.
Brain. 2010 Apr;133(Pt 4):957-72. doi: 10.1093/brain/awq002. Epub 2010 Feb 11.
Splice-modulation therapy, whereby molecular manipulation of premessenger RNA splicing is engineered to yield genetic correction, is a promising novel therapy for genetic diseases of muscle and nerve-the prototypical example being Duchenne muscular dystrophy. Duchenne muscular dystrophy is the most common childhood genetic disease, affecting one in 3500 newborn boys, causing progressive muscle weakness, heart and respiratory failure and premature death. No cure exists for this disease and a number of promising new molecular therapies are being intensively studied. Duchenne muscular dystrophy arises due to mutations that disrupt the open-reading-frame in the DMD gene leading to the absence of the essential muscle protein dystrophin. Of all novel molecular interventions currently being investigated for Duchenne muscular dystrophy, perhaps the most promising method aiming to restore dystrophin expression to diseased cells is known as 'exon skipping' or splice-modulation, whereby antisense oligonucleotides eliminate the deleterious effects of DMD mutations by modulating dystrophin pre-messenger RNA splicing, such that functional dystrophin protein is produced. Recently this method was shown to be promising and safe in clinical trials both in The Netherlands and the UK. These trials studied direct antisense oligonucleotide injections into single peripheral lower limb muscles, whereas a viable therapy will need antisense oligonucleotides to be delivered systemically to all muscles, most critically to the heart, and ultimately to all other affected tissues including brain. There has also been considerable progress in understanding how such splice-correction methods could be applied to the treatment of related neuromuscular diseases, including spinal muscular atrophy and myotonic dystrophy, where defects of splicing or alternative splicing are closely related to the disease mechanism.
剪接调控疗法通过对前信使 RNA 剪接进行分子操控，以期达到基因矫正，是肌肉和神经遗传疾病的一种很有前途的新型疗法——最典型的例子就是杜氏肌营养不良症。杜氏肌营养不良症是最常见的儿童遗传性疾病，每 3500 名新生男婴中就有 1 名患病，会导致进行性肌肉无力、心脏和呼吸系统衰竭以及过早死亡。目前还没有治愈这种疾病的方法，许多有前途的新分子疗法正在被深入研究。杜氏肌营养不良症是由于基因突变破坏了 DMD 基因的开放阅读框，导致必需的肌肉蛋白肌营养不良蛋白缺失。在目前所有针对杜氏肌营养不良症的新型分子干预措施中，也许最有希望的方法是通过“外显子跳跃”或剪接调控来恢复病变细胞中的肌营养不良蛋白表达，即通过反义寡核苷酸来调节肌营养不良蛋白前信使 RNA 的剪接，从而产生有功能的肌营养不良蛋白。最近，这种方法在荷兰和英国的临床试验中显示出了良好的效果和安全性。这些试验研究了将反义寡核苷酸直接注射到单个外周下肢肌肉中，而可行的治疗方法需要将反义寡核苷酸系统性地递送到所有肌肉中，尤其是心脏，最终递送到包括大脑在内的所有其他受影响的组织中。人们在理解如何将这种剪接校正方法应用于治疗相关的神经肌肉疾病方面也取得了相当大的进展，包括脊髓性肌萎缩症和肌强直性营养不良症，这些疾病的剪接或选择性剪接缺陷与疾病机制密切相关。
