LENTIVIRAL GENE THERAPY VECTORS FOR STROKE

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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