Crispr/Cas9个性化基因治疗dystrophin基因N端突变杜氏肌营养不良症

杜氏肌营养不良症(DMD)是一种隐性遗传的肌肉萎缩病，由dystrophin基因突变引起。DMD患者因缺少dystrophin蛋白，出生后肌肉不断损伤，过早消耗肌肉干细胞库，导致进行性的肌肉萎缩。近来，科学家采用Crispr/Cas9技术，将mdx小鼠模型中含有突变的第23位外显子从基因组中剔除，使肌细胞重新表达截短的dystrophin蛋白，并使肌力显著增加。 然而，不同于mdx小鼠的点突变，DMD患者的突变类型十分多样并具有个体特异性。并且目前的研究还仅局限于第51位外显子区域突变，而忽略了较高比例且功能十分重要的N端结构域突变所引起的DMD类型。所以本研究中，我们将针对dystrophin基因N端结构域缺失引起的DMD类型，设计个性化的Crispr/Cas9基因编辑策略，探讨外显子跳跃治疗N端突变DMD的可行性，为DMD的临床研究提供实例分析和重要的理论基础。

Duchenne Muscular Dystrophy (DMD), a recessive X-linked form of muscular dystrophy, arises from mutations in the huge dystrophin gene on the X chromosome that cause premature termination of translation. DMD patients suffer from progressive muscular degeneration and dystrophy at early ages due to lack of dystrophin protein and early exhausting of muscle stem cell pool. Recently, researchers succeeded in removing mutated exon 23 in mdx mouse model by Crispr/Cas9, resulted in partial recovery of functional dystrophin protein in skeletal myofibers and improvement of muscle force. Different from mdx mouse model, mutation types in DMD patients are diversified and personalized, making it difficult to investigate and treat by unified strategy. In this study, we will focus on N-terminus dystrophin mutations and perform personalized genetic therapy using Crispr/Cas9 technique in patient-derived muscle cells. We will provide new feasibility analysis by investigating unprecedented DMD cases and the application of Crispr/Cas9 on DMD genetic therapy will be more illustrated and motivated.