Pre-Clinical Studies of Therapeutic Angiogenesis Induced by Human Hepatocyte Growth Factor (HGF) Gene in Rat and Rabbit Hind Limb Ischemia Models
A novel therapeutic strategy for ischemic diseases using angiogenic growth factors to expedite and/or augment collateral artery development has been proposed. In this study, we examined the feasibility of gene therapy using HGF to treat peripheral arterial disease rather than recombinant therapy. Initially, we examined the transfection of “naked” human HGF plasmid into a rat hindlimb ischemia model. Intramuscular injection of human HGF plasmid resulted in a significant increase in blood flow as assessed by laser Doppler imager. Importantly, at 5 weeks after transfection, the degree of angiogenesis induced by transfection of HGF plasmid was significantly greater than that caused by a single injection of recombinant HGF. As an approach to human gene therapy, we also employed a rabbit hindlimb ischemia model as a preclinical study. Naked HGF plasmid was intramuscularly injected in the ischemic hindlimb of rabbits, to evaluate its angiogenic activity. Intramuscular injection of HGF plasmid produced significant augmentation of collateral vessel development on day 30 in the ischemia model, as assessed by angiography (C100% vs H 245%, P<0.01). Overall, intramuscular injection of naked human HGF plasmid induced therapeutic angiogenesis in rat and rabbit ischemic hind limb models, as potential therapy for peripheral arterial disease.