Gene therapy in peripheral artery disease

Abstract

Introduction: Despite the remarkable progress of medicine and endovascular procedures for revascularization, patients with critical limb ischemia (CLI) remain at high risk for amputation and often have a low quality of life due to pain and ulcers in the ischemic leg. Thus, a novel strategy for generating new blood vessels in CLI patients without treatment options is vital. Pre-clinical studies and Phase I clinical trials using VEGF and fibroblast growth factor (FGF) demonstrated promising results; however, more rigorous Phase II and III clinical trials failed to demonstrate benefits for CLI patients. Recently, two multicenter, double-blind, placebo-controlled clinical trials in Japan (Phase III) and the USA (Phase II) showed the benefits of hepatocyte growth factor (HGF) gene therapy for CLI patients. Although the number of patients included in these trials was relatively small, these results imply a distinct beneficial function for HGF over other angiogenic growth factors in a clinical setting.

Areas covered: In this review, data from Phase I–III clinical trials of gene therapy for patients with peripheral artery disease (PAD) are examined. In addition, the potential mechanisms behind the success or failure of clinical trials are discussed.

Expert opinion: Compared with VEGF and FGF, HGF has a unique molecular effect on inflammation, fibrosis and cell senescence under pathological conditions. These features may explain the clinical benefits of HGF in PAD patients.

Keywords:

• angiogenesis
• fibroblast growth factor
• gene therapy
• hepatocyte growth factor
• peripheral artery disease
• VEGF

Acknowledgments

We thank the members of the Department of Clinical Gene Therapy at Osaka University Graduate School of Medicine for their helpful discussion and technical support. We also thank the American Journal Expert service for language editing manuscript.

Declaration of interest

R Morishita received honoraria, consulting fees and funds from Novartis, Takeda, Shionogi, Astellas, Boehringer Ingelheim, Daiichi-Sankyo and Pfizer. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Notes

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