Peripheral arterial disease (PAD) afflicts approximately 15% of the U.S. population over 55 years of age. After an initial asymptomatic period, patients with PAD typically develop intermittent claudication, which may eventually progress to critical limb ischemia and unrelenting pain, ulceration and amputation. Although exercise, smoking cessation, anti-platelet therapy, cilostazol, statins and revascularization can mitigate symptoms, almost a third of the patients with PAD continue to suffer from intermittent claudication that profoundly impairs their quality of life. Stem cell and progenitor cell (PC) therapy that promotes neoangiogenesis and revascularization is an emerging treatment modality in PAD. Granulocyte -macrophage colony stimulating factor (GM-CSF) stimulates mobilization of hematopoietic and other PCs from the bone marrow. We have demonstrated in a Phase I dose-escalation trial and in a Phase IIA trial in patients with PAD and claudication that GM-CSF mobilizes PCs into the circulation, is safe and results in improvement in claudication. We now propose to investigate the effects of mobilization of bone marrow PCs with two successive administrations of subcutaneous GM-CSF at 3 month intervals in patients with atherosclerotic PAD and walking impairment. Our hypothesis is that GM-CSF will improve walking distance and quality of life in patients with PAD and walking impairment. We will measure improvement in the 6-minute walk test and in walking distance on the treadmill and after two administrations of GM-CSF, three months apart compared to placebo. As secondary outcomes, we will also investigate whether there is further improvement with two compared to single administration of GM-CSF, and whether there is concomitant improvement in quality of life parameters and anklebrachial index.
Our proposal is significant as it addresses a compelling need for alternative therapy for symptomatic PAD that is imposing an increasing burden in the population. It is investigating a unique and novel approach of delivering autologous cell therapy by employing bone marrow PC mobilization and homing to the sites of ischemia. It is supported by robust clinical trial data and if proven successful and effective, will likely provide an important therapeutic option for this population and for a pivotal Phase III trial.