NEW METHODOLOGY FOR VEGF-MEDIATED GENE DELIVERY

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The overall goal of this project is to develop a commercially viable system for selective gene delivery to growing endothelial cells. Growth of endothelial cells underlies angiogenesis that occurs almost exclusively in pathological situations and is promoted by the endothelial cell specific cytokine vascular endothelial growth factor (VEGF). In Phase l we proved the feasibility of a new methodology for VEGF- mediated gene delivery that eliminates direct chemical treatment of the growth factor or DNA. In Phase II studies we will construct transgenes for expression in endothelial cells and we will optimize a VEGF-based vector for highly selective DNA delivery to endothelial cells at angiogenesis sites in vivo. For stimulation of angiogenesis we propose to deliver a transgene encoding VEGF. For inhibition of angiogenesis we will construct transgenes for three apoptosis-inducing proteins fused to the herpesvirus protein vP22 that would ensure intercellular trafficking of the fusion proteins. The proteins we have chosen are: p53, procaspase-8a and granzyme B. Accomplishing these specific aims will provide the in vivo "proof-of- principle" for a novel methodology for VEGF-mediated gene delivery. The optimized VEGF-based DNA vehicle and constructs for fusion proteins will be commercial products for industrial and academic groups involved in receptor-mediated gene therapy. PROPOSED COMMERCIAL APPLICATIONS: The optimized VEGF-based DNA vehicle and constructs for fusion proteins that stimulates or inhibit angiogenesis will be commercial products for industrial and academic groups involved in receptor- mediated gene therapy