LENTIVIRAL GENE THERAPY VECTORS FOR STROKE

慢病毒载体正被开发用于基因治疗：因为它们能够感染并整合到包括未分裂细胞在内的广泛的靶细胞中，而不会产生显著的免疫反应；因此，它们作为大脑或其他神经元组织的基因治疗载体特别有吸引力。我们将测试开发慢病毒载体在脑缺血条件下刺激治疗性血管生成的可行性。我们将构建和测试编码散布因子/肝细胞生长因子(SF/HGF)的慢病毒载体，这是一种同时具有血管生成和神经保护活性的细胞因子。我们将通过插入低氧反应元件(HREs)来修改SF/HGF慢病毒结构，HREs是通过作为低氧诱导因子1(HIF-1)和其他转录因子的结合位点来调节基因表达的序列。我们将通过改变HREs核心序列的结构和位置来优化02介导的转基因表达调控，选择在常氧条件下表达最少，但在低氧条件下快速而显著增加表达的HREs。如果成功，我们将在未来的第二阶段体内研究中使用优化的载体，旨在为中风和其他形式的脑缺血的临床开发和血管生成基因治疗奠定基础。建议的商业应用：不可用

Lentiviral vectors are being developed for gene therapy: because they are capable of infecting and integrating into a wide range of target cells including non-dividing cells without producing significant immunological responses; hence they are particularly attractive as vehicles for gene therapy in the brain or other neuronal tissue. We will test the feasibility of developing lentiviral vectors to stimulate therapeutic angiogenesis under conditions of cerebral ischemia. We will construct and test lentiviral constructs encoding scatter factor/hepatocyte growth factor (SF/HGF), a cytokine that has both angiogenic and neuroprotective activity. We will modify the SF/HGF lentiviral constructs by inserting hypoxia response elements (HREs), sequences that regulate gene expression by serving as binding sites for hypoxia inducible factor 1(HIF-1) and other transcriptional factors. We will optimize 02 - mediated regulation of transgene expression by altering the structure and position of the core sequences of HREs, selecting HREs that minimize expression under normoxic conditions, but produce a rapid and dramatic increase in response to hypoxia. If successful, we will use the optimized vectors in future Phase II in vivo studies designed to be the basis of clinical development and of angiogenic gene therapy for stroke and other forms of cerebral ischemia. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE