经鼻给予病毒载体介导的BDNF基因在脑缺血大鼠中枢神经系统的表达

项目名称： 经鼻给予病毒载体介导的BDNF基因在脑缺血大鼠中枢神经系统的表达

项目编号： No.30870848

项目类型： 面上项目

立项/批准年度： 2009

项目学科： 轻工业、手工业

项目作者： 徐格林

作者单位： 中国人民解放军南京军区南京总医院

项目金额： 31万元

中文摘要： 血脑屏障的存在使大分子很难经血液循环进入中枢神经系统，这一特点成为开发治疗中枢神经系统疾病药物的主要障碍之一。众多的研究表明，具有调节功能的脑源性神经营养因子具有促进神经再生分化，保护神经元免受各种损伤。既往的研究显示用病毒载体携带表达目的基因进入中枢神经系统表达，成为潜在的治疗手段之一。然而血脑屏障阻止基因载体直接进入。单纯疱疹病毒1型具有嗜神经性，在嗅神经和中枢神经系统内长期潜伏。本项目以脑源性神经营养因子基因为目的基因，以四环素调控的复制缺陷的单纯疱疹病毒1型为载体，利用经鼻给药的方式，将重组病毒送至中枢神经系统，治疗缺血性脑卒中。结果显示，经鼻给予病毒载体进入可以脑组织并分布各个区域表达报告基因及目的基因；经鼻给予的病毒载体毒性较低，免疫原性较低；经鼻给予的脑源性神经营养因子可以有效保护缺血后脑组织；经鼻给予的重组病毒表达的脑源性神经营养因子可以有效治疗大鼠大脑中动脉梗塞模型。结果表明，经鼻给予重组单纯疱疹病毒携带的脑原性神经营养因子基因是潜在的脑血管病治疗方法。

中文关键词： 病毒载体；经鼻通路；基因治疗；血脑屏障

英文摘要： The existence of blood brain barrier limits large molecules entering the central nervous system via systematic delivery. It is one of the main obstacles for developing drugs to treat central nervous system diseases. Numerous studies have shown that brain-derived neurotrophic factor can promote nerve regeneration differentiation and protect neurons from various injuries. Previous studies have shown that expression of genes carried by viral vectors in the central nervous system expression may be a potential treatment method. However, dues to the blood-brain barrier, viral vector could not enter the central nervous system directly. Herpes simplex virus type 1 could be long-term potential in the olfactory nerve and central nervous system. The purpose of this project is to develop a tetracycline regulated replication-defective herpes simplex virus type 1 which could carry the gene of brain-derived growth factor via intranasal delivery to treat experimental ischemic stroke. The results showed that intranasal delivery of tetracycline regulated replication-defective herpes simplex virus type 1 entered the central nervous system and distributed in various brain regions; the viral vector following intranasal delivery could express both the reporter and target genes with less toxic and immunogenic; intranasal delivery of brain-derived neurotrophic factor could alleviate the focal brain ischemia via modulating local inflammation; intranasal delivery of the recombinant viral vector through the nasal route can effectively treat rats with middle cerebral artery occlusion. Our results demonstrated that through intranasal delivery of recombinant herpes simplex virus carrying the brain-derived neurotrophic factor gene is a potential treatment of cerebrovascular disease.

英文关键词： Herpes simplex virus 1;intranasal; gene therapy; blood brain barrier