Granulocyte-Macrophage Colony Stimulated Factor (GM-CSF) in Peripheral Arterial Disease

大约15%的55岁以上的美国人患有外周动脉疾病(PAD)。之后 在最初的无症状期，PAD患者通常会出现间歇性跛行，这可能 最终发展为严重的肢体缺血和顽固的疼痛、溃疡和截肢。虽然 运动、戒烟、抗血小板治疗、西洛他唑、他汀类药物和血管重建术可以缓解 症状，几乎三分之一的PAD患者继续遭受间歇性跛行 严重损害了他们的生活质量。干细胞和祖细胞(PC)疗法促进 新生血管生成和血管重建术是PAD的一种新兴的治疗方法。粒细胞-巨噬细胞 集落刺激因子(GM-CSF)刺激骨造血祖细胞和其他PC的动员 骨髓。我们已经在PAD患者的I期剂量递增试验和IIA期试验中证明了这一点 而GM-CSF动员PC进入循环的跛行，是安全的，并导致改善 跛行。 我们现在建议研究连续两次动员骨髓PC的效果。 动脉粥样硬化垫和步行患者每隔3个月皮下注射GM-CSF 减损。我们的假设是GM-CSF将改善PAD患者的步行距离和生活质量 和行走障碍。我们将在6分钟步行测试中测量改善情况，并在 在跑步机上和两次GM-CSF注射后，与安慰剂相比，相隔三个月。作为次要的 结果，我们还将调查是否有进一步的改善，两个与单一 GM-CSF的应用以及生活质量参数和踝臂功能是否有相应的改善 指数。

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.