Nearly 60,000 lower limb amputations occur annually as result of peripheral artery disease (PAD). There are approximately nine million PAD patients in the United States, and PAD results from hardening of the arteries (atherosclerosis), which is a consequence of diabetes, smoking, high cholesterol, or genetic conditions that cause blood vessel disorders.
In a national study that included 550 patients at 80 different sites, patients had bone marrow stem cells removed from their hip bones, and after processing, these stem cells were re-introduced into the leg muscles to stimulate new blood vessel formation. Richard J. Powell, M.D., chief of vascular surgery at Dartmouth-Hitchcock, is the lead investigator in this study, which is presently a three-year, third phase clinical study. The second stage patients showed “remarkable success.”
To delay amputation, patients are usually treated with endovascular therapies like stents or bypass surgery. Patients with the must severe form of PAD, critical limb ischemia (CLI), have arterial blockage that is so severe that stents or bypass surgery are simply not an option, and amputation is the only treatment possibility.
In the words of Dr. Powell: “All of us have stem cells in our bone marrow, and these stem cells can be utilized to repair other parts of our bodies. By taking the patient’s own stem cells and injecting them into the ischemic leg, our hope is that we will them improve the blood flow in that part of the leg/”
The stem cells to which Dr. Powell is referring are the ones that bear two protein markers on their cell surfaces: CD133 and CD34. CD34/CD133 cells are often called “endothelial progenitor cells” or EPCs. EPCs can form endothelial cells, which are the cells that compose capillaries, the smallest and most delicate of all blood vessels. EPCs can also form smooth muscle, which is necessary for the production of arteries, which are surrounded by a ring of smooth muscle that regulates the diameter of the artery and therefore its blood flow. Several studies have shown that EPCs can greatly improve blood flow through the lower limbs in animals with CLI (For example, see Koiwaya H,, et al., J Mol Cell Cardiol.2011;51(1):33-40), but in some studies the stem cells do not survive upon injection and fail to take residence near the vasculature and establish new blood vessels (see Kawamoto A, Asahara T, Losordo DW.Cardiovasc Radiat Med.2002;3(3-4):221-5 & Murasawa S, Asahara T. Physiology (Bethesda). 2005;20:36-42). Also several clinic trials have confirmed the efficacy of EPCs for treating patients with vascular disorders (Lara-Hernandez R, et al., Ann Vasc Surg. 2010 Feb;24(2):287-94; Marfella R, et al., Atherosclerosis. 2010 Feb;208(2):473-9; Zhou B, et al., J Thromb Haemost. 2006 May;4(5):993-1002; Kudo FA, et al., Int Angiol. 2003 Dec;22(4):344-8).
In the study directed by Powell, some patients received injections of their own EPCs and other received a placebo. Six months after treatment, half the patients who had received the placebo died, required an amputation of the affected limb, or had the severity of their leg wounds increase. However of those patients who received the EPC treatment, only about 25% died, required amputation or saw their leg wound worsen. The EPC-treated patients also showed improved blood flow in their legs. Powell summarized these results in this way: “We found that patients who received the stem cell therapy had a significantly lower incidence of amputation at six months than patients who received the placebo.”
Even though, relatively speaking, this study has only a few patients, Powell noticed that he “saw clinically significant improvement in the stem cell-treated patients.” He noted that these data were “compelling enough that there’s no question that the pivotal trial needs to be done as quickly as possible.” The phase three trial has begun and once again, half the patients will receive the placebo and half will receive the stem cell treatment. Powell stated, “we really want to see a therapy that’s effective out to a year. Nonetheless, the results so far are really promising.”