THERAPEUTIC ANGIOGENESIS WITH HUMAN TISSUE KALLIKREIN GENE

Atherosclerosis is a genetic disease that in its natural course causes vascular occlusion, leading to critical reduction in blood supply and tissue hypo-oxygenation and starvation. The European Working Group on Critical Limb Ischemia states that no medical treatment has been shown to alter the natural history of vascular complications. In addition, quality of life indices for these patients are similar to those with terminal cancer. Despite morbidity and mortality associated with amputation, this is often chosen as first-line therapy. Consequently, the need for alternative therapy to treat atherosclerotic patients with critical limb ischemia is compelling. The present proposal, based on recent discoveries of the potent angiogenic action of human tissue kallikrein (HK), is aimed to optimize a method for locally promoting revascularization in a mouse model of atherosclerosis. This approach comprises administering a gene encoding HK under conditions whereby the gene is expressed in targeted cells, thereby promoting angiogenesis. Alternatively, recombinant HK protein or kinin peptides, which are the biologic end-products of kallikrein, will be administered. We foresee that HK will be safer and more effective than any other angiogenic factor as a therapeutic agent for ischemic vascular complications of atherosclerosis.