Gene therapy has been extensively studied in peripheral and cardiac ischemia, heart and vein graft failure, and dyslipidemia, but most clinical trials failed to show their efficacies despite good outcomes in preclinical studies. So far, 2 gene therapies for dyslipidemia and one for critical limb ischemia in peripheral artery disease have been approved. In critical limb ischemia, gene therapy using proangiogenic factors has emerged as a novel therapeutic modality for promoting angiogenesis. Initial researches mainly focused on vascular endothelial growth factor, fibroblast growth factor, or hepatocyte growth factor. After the favorable results of basic research, several phase I and II clinical trials of these proangiogenic factors have shown promising results. However, only a phase III clinical trial of the intramuscular injection of hepatocyte growth factor plasmid DNA has shown successful outcomes, and it was recently approved in Japan for treating patients with critical limb ischemia who have ulcers and for whom no alternative therapeutic options are available. DNA vaccine is another promising modality of gene therapy. An antitumor vaccine suppressing angiogenesis through the inhibition of proangiogenic factors and an antihypertensive vaccine inhibiting the renin–angiotensin system are representative DNA vaccines. The advantage of DNA vaccine is its long-term effectiveness with a few vaccinations; however, the benefits and risks, such as adverse T-cell reaction against self-antigen or long-term side effects, of DNA vaccines should be carefully evaluated. In this review, we discuss the recent advances in proangiogenic gene therapy for critical limb ischemia and DNA vaccine for hypertension.
Biochemical and Immunomorphological Evaluation of Hepatocyte Growth Factor and c-Met Pathway in Patients with Critical Limb Ischemia