Peripheral artery disease (PAD) is caused by atherosclerosis, hardening and narrowing arteries over time due to
buildup of fatty deposit in vascular bed called plaque. Severe blockage of an artery of the lower extremity markedly reduce
blood flow, resulting in critical limb ischemia (CLI) manifested by a variety of clinical syndromes including rest
pain in the feet or toes, ulcer and gangrene with infection. Despite significant advances in clinical care and interventions
for revascularization, patients with CLI remain at high risk for amputation and cardiovascular death. To overcome this
unmet need, therapeutic angiogenesis using angiogenic growth factors has evolved in an attempt to increase blood flow in
ischemic limb. Initial animal studies and phase I clinical trials with vascular endothelial growth factor (VEGF) or fibroblast
growth factor (FGF) demonstrated promising results, inspiring scientists to progress forward. However, more rigorous
phase II and III clinical trials have failed to demonstrate beneficial effects of these angiogenic growth factors to date.
Recently, two multicenter, double-blind, placebo-controlled clinical trials in Japan (phase III) and US (phase II) demonstrated
that hepatocyte growth factor (HGF) gene therapy for CLI significant improved primary end points and tissue oxygenation
up to two years in comparison to placebo. These clinical results implicate a distinct action of HGF on cellular
processes involved in vascular remodeling under pathological condition. This review presents data from phase I-III clinical
trials of therapeutic angiogenesis by gene therapy in patients with PAD. Further, we discuss the potential explanation
for the success or failure of clinical trials in the context of the biological mechanisms underlying angiogenesis and vascular
remodeling, including cellular senescence, inflammation, and tissue fibrosis.
Keywords: Clinical limb ischemia, fibroblast growth factor, gene therapy, hepatocyte growth factor, peripheral artery disease,
therapeutic angiogenesis, vascular endothelial growth factor.
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