Phase II study: Mobilization of progenitor cells in peripheral arterial disease

描述（由申请人提供）： 本申请是对NHLBI参与研究和研究基础设施“大机会”（RC 2）（RFA-OD-09-004）的回应。基础研究成果转化为心、肺、血液疾病的临床治疗，2）心、肺、血液疾病新疗法II期临床试验项目。具体目标。 下肢动脉粥样硬化性外周动脉疾病（PAD）困扰着高达5%的美国人口，其特征在于显著的内皮功能障碍。缺乏适当的可持续疗法导致发病率和死亡率增加。在一项I期研究中，我们研究了使用粒细胞巨噬细胞集落刺激因子（GM-CSF）动员缺血性跛行患者的修复性骨髓细胞。与安慰剂相比，GM-CSF治疗是安全的，动员祖细胞进入循环，并与内皮功能障碍和跑步机运动时间的改善相关。该提案的主要目的是将这些观察结果转化为严重PAD患者的新疗法。 在实验模型中，用集落刺激因子刺激骨髓祖细胞、祖细胞移植和直接注射骨髓来源的细胞似乎可以增强再内皮化和新血管形成，并促进缺血组织的恢复。我们假设，刺激骨髓祖细胞释放将通过增强内皮功能障碍或促进功能性侧支的发育或两者兼而有之来改善PAD患者的症状和结局（图1）。 在一项双盲、安慰剂对照的随机II期研究中，研究骨髓源性祖细胞与GM-CSF动员是否改善PAD患者的跛行症状。拟议的研究将是第一个充分把握度的概念验证II期双盲安慰剂对照研究，以调查祖细胞动员是否会改善PAD的结局，确定潜在的反应机制。这项工作的积极发现将可能导致可广泛应用于治疗难治性PAD的疗法和确定的III期研究。 (End摘要）

DESCRIPTION (provided by applicant): This application is in response to the NHLBI Participation in Research and Research Infrastructure "Grand Opportunities" (RC2) (RFA-OD-09-004). Translation of Fundamental Research Findings into Clinical Treatments for Heart, Lung, and Blood Diseases, 2) Phase II Clinical Trials Program of Novel Therapies for Heart, Lung, and Blood Diseases. SPECIFIC AIM. Atherosclerotic peripheral artery disease (PAD) of the lower extremities afflicts up to 5% of the U.S. population and is characterized by significant endothelial dysfunction. A lack of adequate sustainable therapies results in increased morbidity and mortality. In a Phase I study, we investigated mobilization of reparative bone marrow cells using granulocyte macrophage colony stimulating factor (GM-CSF) in patients with ischemic claudication. Compared to placebo, GM-CSF therapy was safe, mobilized progenitor cells into the circulation, and was associated with improvement in both endothelial dysfunction and treadmill exercise duration. The broad aim of this proposal is to translate these observations into new therapies for patients with severe PAD. Stimulation of bone marrow progenitor cells with colony stimulating factors, progenitor cell transplantation, and direct injection of bone marrow-derived cells appears to enhance re-endothelialization and neovascularization, and promote recovery in ischemic tissues in experimental models. We hypothesize that stimulation of progenitor cell release from the bone marrow will improve symptoms and outcomes in patients with PAD by either enhancing endothelial dysfunction or promoting development of functional collaterals, or both (Figure 1). To investigate whether mobilization of bone marrow-derived progenitor cells with GM-CSF improves symptoms of claudication in patients with PAD in a double-blind, placebo-controlled randomized Phase II study. The proposed study will be the first adequately powered, proof of concept Phase II double-blinded, placebo-controlled study to investigate whether mobilization of progenitor cells will improve outcomes in PAD, defining potential mechanisms of responses. Positive findings from this work will potentially lead to therapies that can be widely applied to treatment of intractable PAD and a definitive Phase III study. (End of Abstract)