新生血管性年龄相关性黄斑变性和糖尿病视网膜病变是重要的致盲性眼病，其病理基础是新生血管形成和血管高通透性。抗血管内皮生长因子(VEGF)治疗有明显疗效，但持续抗VEGF治疗可能导致视网膜萎缩、纤维化等副作用。我们前期研究表明Flt23k可以减少HEK293细胞的VEGF分泌，甲氧苄胺嘧啶(TMP)能够稳定DHFR(DD)-Flt23k的结构和活性。本项目在成功构建DHFR(DD)-Flt23k质粒及新型自身互补腺相关病毒载体(scAnc80)的基础上，探索DHFR(DD)-Flt23k/TMP对视网膜色素上皮细胞条件性调控VEGF分泌的规律；构建大鼠及猕猴眼底新生血管模型，观察scAnc80-DHFR(DD)-Flt23k对其疗效并评估安全性；阐明Flt23k/TMP条件性调控VEGF分泌的相关机制。本项目旨在探索一种条件性调控VEGF的基因新疗法，为临床治疗眼底新生血管性疾病提供新思路。

Neovascular age-related macular degeneration (nAMD) and diabetic retinopathy (DR) are the leading causes of blindness worldwide, which are characterized by the fundus neovascularization and vascular hyperpermeability. The use of anti-vascular endothelial growth factor (VEGF) has a significant treatment effect on these diseases. However, continuous anti-VEGF treatment may lead to retinal atrophy, fibrosis and other side effects. Our previous study demonstrated that Flt23k (a VEGF decoy receptor) enabled to reduce the secretion of VEGF in HEK293 cells. And trimethoprim (TMP) could stabilize the structure and bioactivity of DHFR(DD)-Flt23k. Based on our successful construction of DHFR(DD)-Flt23k plasmid and a new self-complementary adeno-associated virus vector (scAnc80), we will explore the rule of DHFR(DD)-Flt23k/TMP on the conditioned regulation of VEGF secretion in retinal pigment epithelial cells in vitro. Moreover, rat and primate models of fundus neovascularization will be built. And we will validate the therapeutic effects and the safety of scAnc80-DHFR(DD)-Flt23k in animal models of choroidal and retinal neovascularization. Furthermore, we will elucidate the mechanism of Flt23k/TMP conditioned regulation of VEGF secretion. This project aims to probe a new gene therapy for conditioned regulation of VEGF secretion and would provide a new treatment strategy for nAMD, DR and other fundus neovascular diseases in clinic.