肌萎缩侧索硬化(ALS)是一类上、下运动神经元损害并存的致死性神经系统变性病。其确切的发病机制不清，尚无临床有效治疗的原因与目前缺少有效的疾病模型有关。来源于病人特异的诱导性多能干细胞因携带有病人全部的疾病遗传信息，是体外研究ALS发病机制的良好的人源性疾病模型，且可以用于将来的细胞替代治疗。因此，本课题结合前期工作基础，利用非基因整合技术建立不同基因突变的ALS患者特异的ALS-iPS疾病模型并加以验证。在此基础上，运用CRISPR/Cas9介导的定点编辑技术，在iPSC中将突变基因修正成野生型。将基因修正和未修正的iPSC均诱导分化成运动神经元，对照研究突变的基因通过哪些信号通路，引起神经细胞的凋亡与坏死，导致神经退行的病理效应。本研究建立的疾病模型及研究结果，将为研究中国人群ALS发病机制、药物筛选及将来的替代治疗提供良好的平台和实验依据。

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that primarily affects motor neurons (MNs) and has no effective treatment. However, the mechanisms underlying motor neuron loss in ALS are poorly understood. Clinical drug trails have failed partly due to a lack of appropriate disease models, including a lack of access to MNs from ALS patients. Induced pluripotent stem (iPS) cells derived from patients with ALS provide an indispensable resource for in vitro mechanistic studies and for future patient-specific cell-based therapies. . Therefore, to establish a model for use in clinical applications, we generate integration-free iPS cell lines by episomal vectors from ALS patients with different mutations. The ALS-iPS disease model established represents a multifaceted practical platform for studying ALS pathogenesis, for discovering novel therapeutic drugs and for the development of ALS cell replacement therapies.. Using CRISPR/Cas9 genome editing tool to edit the mutation in the patient-derived iPSC. Differentiate ALS patient-specific iPS cells with mutation and corrected mutation into MNs. And further explore the roles of mutation gene on cell survival, apoptosis and necrosis in iPSC-derived motor nuerons from ALS patient. This study will provide a better understanding on the pathogenesis of ALS in Chinese population, and bring new insights on the treatment of ALS.