基于脑胶质瘤骨髓间充质干细胞靶向介导双基因治疗的可视化研究

项目名称： 基于脑胶质瘤骨髓间充质干细胞靶向介导双基因治疗的可视化研究

项目编号： No.81471686

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 李彪

作者单位： 上海交通大学

项目金额： 72万元

中文摘要： 脑胶质瘤发病率高，预后差。临床常规手术及放化疗均不能显著提高患者生存率；而尽管存在自身免疫、血脑及血肿瘤屏障等问题，基因治疗仍是改善其预后的潜在有效新方法。骨髓间充质干细胞（BMSC）无免疫原性，可越过上述屏障向肿瘤迁移。本研究拟在人钠碘同向转运体（hNIS）基因的上游插入可被射线激活的Egr1启动子，同时加上由肿瘤新生血管特异性启动子（TIE-2）启动的抗肿瘤新生血管基因人纤溶酶原kringle 5（K5），构建一个同时表达hNIS和K5的重组慢病毒载体；以该病毒转染BMSC，尾静脉注入脑胶质瘤裸鼠模型，然后实时显像监测体内双基因治疗作用。转染BMSC表达K5，而由静脉给予发射β及γ射线的188Re激活Egr1启动hNIS表达，进而促进188Re摄取，形成hNIS-188Re摄取正反馈，获得188Re和K5蛋白的双重靶向抑瘤功能。项目研究获得结果将为脑胶质瘤辅助治疗及疗效评估提供新方法。

中文关键词： 骨髓间充质干细胞；早期生长反应因子-1；人钠碘同向转运体；TIE-2启动子；人纤溶酶原Kringle；5

英文摘要： Glioblastoma (GBM) is the most common and most aggressive primary brain tumor. Despite aggressive surgery, radiotherapy and chemotherapy, the prognosis of GBM patients remains poor. Gene therapy is increasingly being explored as a novel therapeutic option. It has been reported that bone marrow mesenchymal stem cells (BMSC), with the immunological compatibility, can target GBM cells by penetrating blood-brain barrier and blood-tumor barrier. In this study, a dual-regulatory element lentiviral vector (Lv-TIE-2-K5-Egr1-hNIS) will be constructed, which contains: 1) kringle 5 (K5) of human plasminogen, an angiogenesis inhibitor, driven by the promoter of TIE-2 gene that overexpressed in the tumor endothelial cells; 2) human sodium iodide symporter body (hNIS) gene, driven by a radiation-activated gene promoter, Egr1. The Lv-TIE-2-K5-Egr1-hNIS transduced BMSCs will be transplanted into the GBM-bearing nude mice and further be recruited to the tumor microenvironment, inducing the K5 overexpression. 188Re will then be injected intravenously, leading to the hNIS expression in BMSCs within the tumor by activation of the Egr1 promoter through β and γ rays. More expression of hNIS protein in tumor tissue will result in more tumor-spefic uptake of 188Re, forming a postive feedback. We expect that this dual-regulatory element lentivirus could incorparate the anti-angiogenesis therapy by K5 protein overexpression and the radiohtherapy by tumor-spefic 188Re-uptake via one single vector. Noninvasive 188Re micro-SPECT imaging will be used to assess the treatment response dynamically. If successful, this lentivirus-based gene therapy will provide a new adjuvant therapeutical option for GBM patients.

英文关键词： bone marrow derived mesenchymal stem cell;early growth response gene 1(Egr1);the human sodium iodide symporter(hNIS);Tyrosine kinase with immunoglobin-like and EGF-like domains 2 (TIE-2) promoter;the human plasminogen kringle 5(K5)