Clinical Trials within U.S.: Peripheral Vascular Disease

LOWER—EXTREMITY PERIPHERAL ARTERY disease (PAD) is a common, debilitating, and potentially life—threatening illness affecting nearly 10 million people in the United States and fully 10 percent of those older than 60 years. PAD unfortunately remains an underrecognized disease, however, and can be difficult to treat. Obstructive PAD is most commonly caused by atherosclerosis and can initially manifest as intermittent claudication, defined as leg muscle pain with walking that is relieved with rest. PAD may progress to critical limb ischemia (CLI), defined by pain at rest, skin ulcers, and gangrene. In the latter condition, limb amputation is threatened unless blood flow can be restored.

Risk factor modification, exercise therapy, and antiplatelet, antihypertensive, and antilipid therapy are mainstay therapy for PAD. Unfortunately, a significant number of patients fail medical therapy. Mechanical revascularization includes invasive surgical bypass and minimally invasive cath—eter-based approaches. Surgical bypass to restore blood flow may be limited by arteries that are too small and diseased to successfully graft into. Patient comorbidities also make surgical options risky. Use of percutaneous revascularization such as angioplasty and stenting is limited by small, distal, diseased arteries; technical difficulty accessing the target artery; and high restenosis rates. Incomplete revascularization may result in poor distal arterial runoff and inadequate tissue perfusion. Amputation may be the only treatment option for nonhealing ulcers or gangrene in many patients. Afflicted patients may have significant physical and emotional disabilities. Psychological testing of patients with CLI shows quality—of-life indices similar to those of patients with terminal malignancy. The magnitude of the clinical problem, the effect of the disease on quality of life, and limitations of conventional treatment make this patient subset ideally suited for clinical investigation of novel regenerative cell—based therapies.

Stem cells can differentiate into nearly any cell type and can self—renew indefinitely. Adult progenitor cells differ from stem cells in that they have reduced differentiation capacity and lack the ability to self—renew. However, adult progenitors are more easily accessible, have significant proliferative capability, and can generate large numbers of mature cells. Hypoxia results in the enhanced ability of certain “endothelial” progenitor cells (EPCs) to ameliorate ischemia. EPCs are typically defined by their expression of certain surface markers such as CD34+, CD133+, and Flk-1. As EPCs differentiate, they acquire mature endothelial lineage markers such as vascular endothelium cadherin, CD31+, and von Willebrand factor. Adult—derived bone marrow and circulating progenitor cells have been the focus of current human trials to treat severe, obstructive PAD.