Elsevier

Cytotherapy

Volume 15, Issue 10, October 2013, Pages 1245-1252
Cytotherapy

Original paper
Hematopoietic stem cell transplantation
Peripheral blood-derived autologous stem cell therapy for the treatment of patients with late-stage peripheral artery disease—results of the short- and long-term follow-up

https://doi.org/10.1016/j.jcyt.2013.05.017Get rights and content

Abstract

Background aims

Regeneration of the occluded peripheral arteries by autologous stem cell therapy is an emerging treatment modality for no-option patients with peripheral artery disease (PAD). The purpose of this study was to assess safety and efficacy of in vitro–expanded, peripheral blood-derived, autologous stem cells (VesCell) in no-option patients with PAD.

Methods

A phase II, open-label, randomized clinical study was performed on 20 patients to investigate the safety and efficacy of VesCell therapy at 1 and 3 months of follow-up. The long-term (2 years) efficacy of the therapy was also evaluated.

Results

No side effects of VesCell therapy were found. During the 3 month follow-up in the control group, one death occurred and six major amputations were performed; in the treated group, there were no deaths or major amputations. The difference of limb loss is significant between the two groups. At 2-year follow-up in the control group, two deaths and six major amputations occurred; in the treated group, there were three major amputations. At 3-month follow-up, the change in hemodynamic parameters showed a significant increase in the treated group over the control group; in the treated group, further improvement was detected at 2 years. As the result of the VesCell treatment, change in pain score, wound healing and walking ability test showed an improvement compared with the control group; at 2 years, incremental improvement was observed.

Conclusions

Peripheral blood-derived, in vitro–expanded autologous angiogenic precursor therapy appears to be a safe, promising and effective adjuvant therapy for PAD patients.

Introduction

Peripheral arterial disease (PAD) is a disease process involving the obstruction of arteries in the limbs as a result of atherosclerosis and inflammatory processes. It causes either acute or chronic ischemia, typically of the legs. The major causes of PAD in the Western world are atherosclerosis and diabetes, but ageing, smoking, hyperlipidemia and hypertension are also important risk factors. The prevalence of PAD in the United States is estimated to be 10–14 million, and the disorder affects men and women equally 1, 2.

Despite intensive research, pathomechanism-related therapy is still not available, and surgical reconstruction is applicable only to large vessels. Stem cell therapy is a potential breakthrough in this group of disorders, primarily because smaller peripheral vessels can be regenerated, which have been inaccessible by surgery and/or interventional radiology.

Initial presentation of PAD is an intermittent claudication with pain in the calf that is elicited by exertion and relieved with a few minutes of rest. Critical limb ischemia (CLI) is the end stage of lower-extremity PAD in which severe obstruction of blood flow results in ischemic rest pain, ulcers, gangrene and a significant risk for limb loss. Approximately 15–30% of patients with lower-extremity PAD progress from intermittent claudication to CLI over the course of their disease (3). The prognosis of patients with advanced PAD and chronic CLI is poor. Patients with CLI represent approximately 1% of the total number of patients with PAD, with overall mortality approaching 50% within 5 years and 70% in 10 years (4). The estimated number of patients with CLI is between 1.5–2 million in Europe and the United States (5).

Leg revascularization procedures work well for patients with CLI by providing sufficient blood flow to relieve rest pain and heal skin lesions. If not surgically revascularized, patients with CLI can lose limbs or acquire other potentially fatal complications caused by gangrene progression or sepsis. Approximately 20–30% of patients with CLI are not considered candidates for vascular surgery or interventional endovascular procedures; therefore, amputation is often the only choice (no-option patients). Primary amputation is considered when there is an absence of distal vessels, especially in the case of advanced distal ischemia associated with a low ankle-brachial index (ABI) value (<0.3) (6). The reported primary amputation rates among patients with CLI vary between 10–40% (7). There is an urgent need for better treatment modalities because major amputations carry a grave prognosis.

Compared with current conventional therapy, which usually involves the administration of a drug or implantation of a device, autologous cell therapy represents a more physiological way. There is solid evidence that bone marrow-derived mononuclear cell (BM-MNC) implantation into ischemic limbs 8, 9, 10 or myocardium (11) promotes collateral vessel formation with incorporation of endothelial progenitor cells into new capillaries.

In some studies, granulocyte colony-stimulating factor (G-CSF) pre-medication was used 12, 13 to enhance migration of stem cells from the BM into the peripheral blood. However, this procedure is not only costly but it may also be harmful to patients with or cardiac patients (14).

In contrast to BM-derived cells, the administration of peripheral blood-derived angiogenic cell precursors (ACPs) may have several advantages (15).

In vitro–expanded, peripheral blood-derived autologous angiogenic cell precursors (VesCell, Theravitae Co Ltd, Ness-Ziona, Israel) were previously used successfully for experimental myocardial infarction and clinically for congestive heart failure therapy and in a pilot CLI study 15, 16, 17.

The aim of this open-label, randomized phase II pilot study was to prove the short-term (3 months) safety and efficacy of VesCell, administered intramuscularly into the ischemic gastrocnemius muscle of patients with late-stage PAD, who were treated with maximal medical therapy and did not have intravascular or operative revascularization option. To get the long-term efficacy data, some treated patients were also investigated at 2 years of follow-up.

Section snippets

Study design

Patients visiting Kelen Hospital, Budapest, and Semmelweis University Faculty of Medicine, Department of Cardiovascular Surgery, Budapest, were screened for the study. Twenty-two late-stage no-option patients with PAD meeting inclusion and exclusion criteria were enrolled into the study. Accordingly, patients with Fontaine III-IV stages, ABI <0.45 or transcutaneous oxygen pressure (TcPO2) <40 mm Hg were included into the study, whereas subjects with meaningful suprapopliteal occlusion were

Patient baseline characteristics

The patients' mean age was 61.8 ± 10.4 years; 13 of the patients were male. Ten lumbar sympathectomies and three vascular reconstruction surgeries had been performed earlier. Fifteen patients had gangrene at baseline. Two patients in both groups had amputation (three crural, one femoral) before the study. Diabetes mellitus was found in 12 patients; seven were insulin-dependent. In the background of late-stage PAD there was Buerger disease in one patient and peripheral arterial embolization in

Discussion

Despite technical development in interventional radiological and surgical revascularization procedures, there is a substantial number of patients with PAD and CLI in whom major amputation must be considered as the only final option (4). However, recently, there were several studies of auto-transplantation of BM-MNC 8, 9, 10 and G-CSF–mobilized peripheral blood MNC in patients with CLI demonstrating the improvement of ischemic status 12, 13. Therefore, these therapeutic modalities may enhance

Acknowledgments

This work was supported by the National Development Agency (grant No. KMOP-1.1.2–07/1-2008–0003).

Disclosure of interests: The authors have no commercial, proprietary, or financial interest in the products or companies described in this article.

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