SBIR-STTR Award

Vascular endothelial growth factor (VEGF) is an endothelial cell-specific mitogen capable of potently stimulating new blood vessel growth (angiogenesis). VEGF-165 and VEGF-121 are two different isoforms of the factor generated from the human VEGF gene by alternative splicing. VEGF-121 differs from VEGF 165 in that VEGF-121 does not bind. VEGF-165 has been shown to promote collateral-dependent blood flow in an animal model of peripheral arterial insufficiency, and has been proposed as a potential agent for the treatment of peripheral arterial disease. Since the heparin-binding region in VEGF-165 has been implicated as being involved in the inactivation and clearance of the factor in vivo, the long term goal of this project is to determine if VEGF-121, which lacks the heparin-binding sequences, shows advantages over VEGF-165 as a potential therapeutic agent. In Phase I of the project, recombinant versions of VEGF-121 and VEGF-165 will be generated and tested side-by-side in a rat model of peripheral arterial insufficiency. If VEGF-121 shows efficacy in these two in vivo experiments, then Phase II studies will be initiated that will in part compare VEGF-121 and VEGF-165 effects in dose-ranging experiments in vivo using various routes of drug administration.

Thesaurus Terms:
blood vessel disorder, cardiovascular disorder chemotherapy, drug screening /evaluation, peripheral blood vessel, vascular endothelial growth factor artery, blood flow measurement, disease model, dosage, protein isoform, vascular endothelium laboratory rat, protein purificationNational Heart, Lung and Blood Institute (NHLBI)

Vascular endothelial growth factor (VEGF) is a highly endothelial cell-specific mitogen capable of stimulating new blood vessel growth (angiogenesis) and collateral- dependent blood flow in vivo. Because of these properties, VEGF has been proposed as a potential pharmacological therapy for the treatment of peripheral arterial disease. Among the five different splice variant isoforms of VEGF, only the shortest (VEGF121) lacks the ability to bind heparin-like molecules. Experiments during Phase I of the project established that VEGF121, like other VEGF isoforms, is active in vivo for the promotion of collateral-dependent blood flow. In addition, consistent with its lack of heparin binding, VEGF121 was found to display pharmacokinetic and clearance characteristics that may confer particular therapeutic advantages to the use of this isoform. During Phase II of the project, VEGF121 will be advanced toward eventual clinical testing of efficacy and of validation for these potential advantages. In particular, a manufacturing process will be developed for the drug. Further experiments will also be undertaken to better define the effects of VEGF121 in an animal model of peripheral arterial insufficiency. PROPOSED COMMERCIAL APPLICATION: The research is ultimately aimed at developing a therapeutic agent for the treatment of peripheral arterial disease.

Thesaurus Terms:
angiogenesis, cardiovascular agent, drug design /synthesis /production, peripheral blood vessel disorder, protein engineering, recombinant protein, vascular endothelial growth factor cardiovascular disorder chemotherapy, drug screening /evaluation, fermentation, nonsurgical revascularization, transfection vector protein purification