Cell-Based Therapies for Peripheral Arterial Disease

Atsuhiko Kawamoto

doi:10.4172/2157-7633.1000234

Abstract

Chronic critical limb ischemia (CLI) is defined as the end-stage of lower limb ischemia due to atherosclerotic peripheral arterial disease (PAD) or vasculitis including thromboangitis obliterance (Buerger’s disease). CLI patients are at very high risk of amputation and experience poor physical function, leading to severe morbidity and mortality despite the development of surgical bypass technique or endovascular approach. Therefore, exploring novel strategies for blood flow recovery of ischemic limbs is urgently needed for patients with CLI. Although researchers initially focused on gene therapy using proangiogenic growth factors, recent discovery of somatic stem/progenitor cells including bone marrow (BM)-derived endothelial progenitor cells (EPCs) and mesenchymal stem cells (MSCs) has drastically developed the field of therapeutic angiogenesis for CLI. In 2002, the first clinical trial of intramuscular injection of BM-derived mononuclear cells (BM-MNCs) demonstrated safety, feasibility and efficacy for CLI patients. Since then, at least 50 clinical trials of BM- and peripheral blood (PB)-derived MNC therapy, 4 trials of CD34+ cell (an EPC-enriched fraction) therapy and 8 trials of MSC therapy have been performed for CLI. Overall, the results of these early phase clinical trials regarding stem/progenitor cell therapies may be safe, feasible and effective. However, only few late-phase clinical trials have been conducted. Currently, at least 3 phase III trials including 2 trials using BMMNCs and 1 trial using granulocyte-colony stimulating factor (G-CSF)-mobilized PB-MNCs are ongoing. This review provides an overview of the preclinical and clinical reports to demonstrate the usefulness and the current limitations of the cell-based therapies.

Highlights

Peripheral arterial disease (PAD) is commonly referred to ischemia of extremities secondary to atherosclerotic occlusion
An additional cause of PAD is vasculitis including thromboangitis obliterance (TAO) (Buerger’s disease), which can lead to severe limb ischemia
We provide an overview of the basic characteristics and clinical trials of cell-based therapies for PAD and discuss regarding the current problems and the future perspectives

Summary

Introduction

Peripheral arterial disease (PAD) is commonly referred to ischemia of extremities secondary to atherosclerotic occlusion. Doubleblind, placebo-controlled clinical trial of HGF plasmid in patients with CLI, the primary endpoints including rest pain and ulcer size significantly decreased in the HGF treated group compared with the placebo group [26]. A total of 40 patients with CLI were enrolled, received either intraarterial administration of BM-MNCs or placebo, and at the end of 3 months, the placebo group were crossed over to active treatment (an initial administration of BM-MNCs) and the active group received the second administration of BM-MNCs. This study demonstrated the dosedependent improvement in ulcer healing and significant reduction in rest pain, despite no difference in limb salvage rate, amputation-free survival and the primary end point which was an increase in ABPI

25 BM-MNCs

Study design Patient series

Findings

Conclusions