Antisense oligonucleotide induced exon skipping as a treatment for Duchenne Muscular Dystrophy

Duchenne肌营养不良症(DMD)是影响男孩的最常见的严重肌肉萎缩疾病。营养不良蛋白基因的缺陷(典型的移码或无义突变)阻止了任何功能性蛋白质的合成。Becker肌营养不良症(BMD)是一种较轻微的疾病，也是由dystrophin基因缺陷引起的，但在这些情况下，突变通常是框内缺失，允许合成一些功能蛋白。由于目标(肌肉纤维)的性质以及基因的大小和复杂性，抗肌营养不良蛋白基因替代疗法一直存在显著的局限性。该项目将研究在表达dystrophin的细胞中的另一种遗传方法(该基因在各种细胞类型中以不同的方式转录和处理)，从而使用反义寡核苷酸来重定向DMD突变区域中dystrophin前-mRNA的处理。虽然DMD突变仍然存在于基因水平，但致病突变将在Dstrophin Pre-mRNA的加工过程中被移除。一旦去除了无义突变或从DMD转录本中恢复了阅读框架，所产生的基因工程的dystrophin mRNA就可以被翻译成功能类似Becker的蛋白质。

Duchenne muscular dystrophy (DMD) is the most common severe muscle wasting disease that affects boys. A defect in the dystrophin gene (typically a frameshift or nonsense mutation) precludes the synthesis of any functional protein. Becker muscular dystrophy (BMD) is a milder condition that also arises from defects in the dystrophin gene but in these cases, the mutations are usually in-frame deletions that allow some functional protein to be synthesised. There have been significant limitations to dystrophin gene replacement therapies, due to the nature of the target (muscle fibres) and the size and complexity of the gene. This project will investigate an alternative genetic approach in cells expressing dystrophin (this gene is transcribed and processed differently in a variety cell types), whereby antisense oligonucleotides are used to redirect the processing of dystrophin pre-mRNA in the region of the DMD mutation. Although the DMD mutation would still be present at the gene level, the disease-causing mutation would be removed during the processing of the dystrophin pre-mRNA. Once a nonsense mutation has been removed or the reading frame restored from a DMD transcript, the resultant engineered dystrophin mRNA could be translated into a functional Becker-like protein.