研究基因编辑技术治疗小鼠长QT综合征的效果

先天性长QT综合征(LQTS)是一种常染色体遗传性心脏病，需要终身用药。基因编辑技术可以在体内纠正遗传突变，具有长期治疗效果。申请人前期建立了多个长QT综合征的干细胞模型，并且开发出了简单高效的基因编辑技术。在本项目前期试验中，已经将病人特异的突变引入到小鼠Scn5a基因中，建立了长QT综合征小鼠模型。本项目拟研究两种基因编辑技术对小鼠模型的治疗效果，具体研究内容包括：1）利用碱基编辑技术对小鼠模型进行治疗，评估对心脏的编辑效率和治疗效果；2)利用新出现的引导编辑技术（Prime editing）对小鼠模型进行治疗，评估对心脏的编辑效率和治疗效果；3）研究治疗过程中是否会引发心律紊乱。本研究将为先天性长QT综合征的基因治疗提供依据，也为其他先天性心肌病的治疗提供借鉴。

Congenital long QT syndrome (LQTS) is an autosomal inherited heart disease, which requires lifelong medication. Genome editing technology can correct genetic mutation in vivo and has long-term therapeutic effect. The applicant has previously established several stem cell models of long QT syndrome and developed simple and efficient gene editing techniques. In the preliminary experiment of this project, the patient specific mutation has been introduced into the SCN5A gene of mice to establish a long QT syndrome mouse model. This project plans to study the therapeutic effect of two genome editing technologies on mouse model, the specific research contents include: 1) using base editing technology to treat mouse model and evaluate the editing efficiency and therapeutic effect on the heart; 2) using the novel prime editing technology to treat the mouse model and evaluate the editing efficiency and therapeutic effect on the heart; 3) to study whether there will be arrhythmia during the treatment. This study will provide the basis for gene therapy of congenital long QT syndrome and other congenital cardiomyopathy.