视网膜色素变性（Retinitis Pigmentosa，RP）是全球致盲率最高的遗传性眼科疾病。中国RP患者比例高达1/1000，其中有很大一部分病人是由于视紫红质基因Rhodopsin（RHO）显性点突变引发。传统药物治疗和新兴的基因替代疗法无法彻底治愈该显性遗传疾病。项目组的前期研究数据和最近的领域进展均显示单碱基编辑器ABE具有很好的特异性。通过分析我校中山眼科中心RP患者基因的突变信息，获得并验证了若干有望利用ABE系统进行修复的RHO点突变（C∙G→T∙A）位点。本项目将系统地构建和筛选高效的双AAV介导Split-ABE组合，利用自主制备的RHO点突变（C∙G→T∙A）的细胞和小鼠模型，系统地研究双AAV介导Split-ABE在体内的编辑效率和安全性。研究结果将为RP等视网膜相关点突变遗传性疾病提供新的治疗策略，为基因编辑创新疗法的临床应用提供重要的科学依据。

Retinal pigmentation (RP) is the most common hereditary eye disease with the highest blindness rate in the world. The proportion of RP patients in China is as high as 1/1000, and a large proportion of them are caused by dominant point mutation of rhodopsin (RHO) gene. Neither traditional drugs nor emerging gene replacement therapy can cure the dominant hereditary disease thoroughly. Recent studies and our previous data showed that the base editor ABE is more specific in gene editing. After analysing the gene mutation information of RP patients in Zhongshan Ophthalmic Center of Sun Yat-sen University, we obtained several RHO point mutation sites (C∙G→T∙A) which were expected to be corrected by ABE system. In this project, we will systematically construct and screen several efficient combination of Slipt-ABE mediated by double AAVs, and then test the editing efficiency and safety of double AAV-mediated Split-ABE in vivo by using RHO point mutation (C∙G→T∙A) cell and mouse RP models. The results will provide a new therapeutic strategy for retinal point mutation genetic diseases such as RP. It will also provide an important scientific basis for the clinical application of innovative gene editing therapy.