HGF Gene Therapy for Therapeutic Angiogenesis in Peripheral Artery Disease

Abstract

Peripheral arterial disease (PAD) is a chronic arterial occlusive disease in the lower and upper extremities due primarily to atherosclerosis. The clinical consequences of severe PAD and critical limb ischemia include pain while walking (intermittent claudication), pain at rest, and the loss of tissue integrity in the distal ischemic limbs. Moreover, PAD is strongly associated with elevated morbidity and mortality with cardiovascular disease. In general, the best therapeutic option for chronic arterial occlusion is revascularization with percutaneous transluminal angioplasty or surgical bypass. Unfortunately, some patients are poor candidates for revascularization due to the anatomical distribution of severe stenosis, calcification of the artery, poor outflow in the distal lower limb, and medical comorbidities. Thus, specific strategies are needed to deliver sufficient blood flow to eliminate the symptoms in PAD patients. Many studies have been performed using cell-based therapy (e.g., endothelial progenitor cells, bone marrow mononuclear cells, and mesenchymal stem cells) and gene therapy (e.g., vascular endothelial growth factor, fibroblast growth factor, and hepatocyte growth factor (HGF)) for the induction of angiogenesis. Among them, our group has been working on the delivery of the HGF gene into ischemic limbs. It can stimulate angiogenesis without the induction of vascular inflammation and vascular permeability. In this review article, we focus on the results of clinical trials using HGF gene transfer and discuss the molecular differences between HGF and other growth factors.