Targeted Corrective Gene Conversion (TCGC): Application in DMD mutations and delivery to dystrophic (mdx) muscle

肌肉萎缩症是一种遗传性疾病，会导致肌肉萎缩和严重残疾。最严重的形式导致新生儿早期死亡，但在儿童中诊断出的大量形式表现出早期轻度症状，并在少年和青年中稳步发展为严重致残形式。也许这些营养不良症中最具破坏性的是杜氏肌营养不良症（DMD）。每3300名男孩中就有1人患有这种疾病，他们在5岁左右出现症状，直到青少年早期坐轮椅。DMD男孩接受主要的临床和手术治疗，目前只对他们的生活提供了微小但显著的改善。杜兴男孩的平均死亡年龄为22岁。DMD的病因已经知道了近20年，它是由肌肉细胞产生的肌营养不良蛋白的单一组成部分的缺陷。一般来说，患有DMD的男孩都有肌营养不良蛋白，这种蛋白缺少一个重要的部分，可以防止运动时肌肉的分解。因此，DMD男孩的所有肌肉在他们的一生中慢慢分解，直到他们死亡，因为帮助吸气的肌肉（横膈膜）不再能够帮助他们呼吸。肌肉成分肌营养不良蛋白是由一种基因（dys基因）产生的，而肌营养不良蛋白的缺陷是由dys基因的缺陷引起的。如果DMD男孩的dys基因缺陷能够得到纠正，他们的肌营养不良蛋白也可能得到纠正，他们的肌肉分解也可能得到预防。我们已经能够纠正患有DMD的老鼠肌肉细胞中的dys基因。我们希望改进这项技术，让肌肉通过基因矫正纤维得到矫正，从而为治疗人类DMD奠定基础。通过这种方式，我们希望显著改善和延长这些男孩的生命，甚至治愈DMD和其他遗传性肌肉疾病

The muscular dystrophies are inherited diseases that lead to muscle wastage and severe disabilities. The most severe forms result in the early death of newborns, but a large number are diagnosed in children showing early mild symptoms and progress steadily to severe disabling forms in the juvenile and young adult. Perhaps the most devastating of these dystrophies is Duchenne Muscular Dystrophy (DMD). This condition affects 1 in 3,300 boys, who show symptoms at around 5 years of age until wheelchair confinement by early teens. DMD boys undergo major clinical and surgical treatments which at present only provide small but significant improvements to their lives. The median age at death for Duchenne boys is 22 years. The cause of DMD has been known for almost 2 decades and is a defect in just a single component of muscle, Dystrophin which is produced by muscle cells. In general, boys with DMD possess Dystrophin which is missing an important part that prevents the breakdown of muscles during activity. As a consequence, all the muscles in DMD boys slowly break down over their lifetime until they die because the muscle which helps in drawing breath (Diaphragm) is no longer capable of helping them to breathe. The muscle component Dystrophin is produced by a gene (the dys gene) and the defect of Dystrophin is caused by a defect in the dys gene. If the dys gene defect was able to be corrected in boys with DMD, their Dystrophin may also be corrected and the breakdown of their muscle prevented. We have been able to correct the dys gene in muscle cells from a mouse with DMD. We wish to improve this technology and allow muscle to be corrected with genetically corrected fibres to form a basis for treatment of human DMD. In this way we hope to significantly improve and lengthen these boys' lives and even lead to a cure for DMD and other genetic muscle disease