Yokota T, Duddy W, Partridge T
Children's National Medical Center, Center for Genetic Medicine, Washington, DC 20010, USA.
Acta Myol. 2007 Dec;26(3):179-84.
Exon skipping is one of the more promising therapeutic options for Duchenne Muscular Dystrophy (DMD). The idea is to use antisense oligonucleotides to splice out selected exons from the pre-mRNA, at or next to the mutation site, so as to generate a translatable transcript from the mutant dystrophin gene. In principle, the majority of DMD mutations can be rescued by targeting selected exons. Recent developments of antisense oligonucleotides (AOs) such as 2O-methylated antisense oligonucleotides (2OMeAOs) or phosphorodiamidate morpholino oligomers (morpholinos, PMOs) have made it possible to restore dystrophin expression body-wide in dystrophic mice and dystrophic dogs by single or multi-exon skipping with no obvious side-effect. Since such treatment would, in many cases, require bespoke design of AOs, it is important to demonstrate treatment of a variety of mutations in dystrophic animals. In-frame deletion patterns usually result in a mix of Duchenne and milder Becker Muscular Dystrophy (BMD), but the ratio of Duchenne to Becker varies between patterns, and this provides useful information for selection of the exons that might most profitably be targeted. This review summarizes recent progress in exon skipping therapy and discusses future strategies.
外显子跳跃是杜氏肌营养不良症（DMD）最有前景的治疗选择之一。其原理是使用反义寡核苷酸在突变位点或其附近从信使前体核糖核酸（pre-mRNA）中剪接出选定的外显子，从而从突变的肌营养不良蛋白基因产生可翻译的转录本。原则上，通过靶向选定的外显子，大多数DMD突变都可以得到挽救。反义寡核苷酸（AOs）如2'-O-甲基化反义寡核苷酸（2OMeAOs）或吗啉代磷酰胺二聚体（吗啉代，PMOs）的最新进展使得通过单外显子或多外显子跳跃在营养不良的小鼠和犬类体内恢复肌营养不良蛋白的全身表达成为可能，且无明显副作用。由于在许多情况下，这种治疗需要定制设计AOs，因此在营养不良动物中证明对多种突变的治疗效果很重要。框内缺失模式通常会导致杜氏肌营养不良症和症状较轻的贝克肌营养不良症（BMD）混合出现，但杜氏肌营养不良症与贝克肌营养不良症的比例在不同模式之间有所不同，这为选择可能最有益靶向的外显子提供了有用信息。本综述总结了外显子跳跃疗法的最新进展并讨论了未来策略。
