Gene Therapy for Angiogenesis

Atherosclerosis and endothelial dysfunction are responsible for the pathophysiologic basis of the spectrum of cardiovascular disorders including ischemic heart disease (IHD), the leading cause of morbidity and mortality in the United States. There have been major advances including the use of pharmacotherapy, coronary and peripheral percutaneous transluminal interventions (PTI), coronary and peripheral bypass surgery, and primary/secondary prevention measures. There are, however, multiple unmet needs: IHD refractory to medical therapy and unsuitable for revascularization; critical limb ischemia (CLI) unsuitable for PTI or surgery; restenosis; ischemic/diabetic neuropathy; and heart failure. Cardiovascular gene therapy (GT) with vascular endothelial growth factor (VEGF) and other angiogenic factors such as fibroblast growth factor (FGF) has yielded improved perfusion and reduced ischemia in preclinical models of IHD. Several preclinical studies, phase I and II clinical trials, have shown the safety and therapeutic potential of GT in the treatment of IHD, peripheral arterial disease (PAD), restenosis, and ischemic and diabetic neuropathy, pointing to the need for carefully designed phase III clinical trials, which would have to address the advantages and disadvantages of the diverse delivery strategies, candidate genes, and methods of functional assessment of angiogenesis, while selecting relevant primary and secondary