脊髓性肌萎缩症(SMA)是常见的常染色体隐性遗传病之一，其致病基因为运动神经元生存基因（SMN），SMN基因存在两种同源性极高的拷贝SMN1、SMN2，二者仅有5个碱基的细微差异。在SMN1缺失的情况下，SMN2剪接异常导致产生的全长蛋白极少,不能弥补SMN1的功能而发病。目前关于SMA发病机制研究主要集中在SMN异常剪接的机制方面，SMA是剪接体病的典型代表，一直是研究的焦点。我们前期建立了直接源于SMA患者及对照的无创性尿液细胞系，进行了SMN蛋白表达、定位及药物干预等系列研究，并建立了SMA患者及其异卵双生健康同胞的iPS细胞模型。本项目将针对SMN1与SMN2基因的 5个碱基差异点，采用TALEN技术对SMA患者iPS细胞模型进行基因修饰，进一步在运动神经元水平探讨"SMN基因异常剪接"这一核心问题，为阐明本病的发病机制及探索有效的防治手段提供理论依据。

Spinal muscular atrophy (SMA) is a common autosomal recessive inherited neurological disease, which is caused by the mutations in survival motor neuron gene 1 (SMN). Interestingly, SMN2 gene, a highly identical homolog of SMN1 with only 5 nucleotide differences between them, encodes only a small part of full-length SMN protein, which cannot compensate for the homozygous loss of SMN1and gives rise to the development of SMA. To date, many studies mainly focused on the mechanisms of abnormal gene splicing of SMN2 gene. Recently, we successfully established non-invasive urine-derived cell lines from SMA patients and health controls for further research of SMN expression and drug screening. Besides, we obtained the induced pluripotent stem cells (iPS) reprogrammed from urine cells from non-identical twins in vitro. In the present study, we intend to perform the gene correction of SMN2 gene to substitute the 5 nucleotide differences by TALEN technology, and further explore the mechanisms of SMN2 gene splicing on induced motor neuron level, from axonal growth, SMN expression to transcriptome analysis, and shed some light on the fundamental mechanism and effective treatment of SMA.