Utility of Autologous and Allogeneic Cell Therapy for Peripheral Arterial Disease

描述（由申请人提供）： 印第安纳州地区心血管细胞治疗中心（IRCCTC）将扩展心血管细胞治疗研究网络的工作，特别是在外周动脉疾病（PAD）领域。严重肢体缺血（CLI）每年导致至少50，000例截肢，估计每年的成本为43亿美元。在最近的I/II期试验中，我们已经证明了安全性， 肌内注射自体骨髓单个核细胞（ABMNC）治疗CLI患者的可行性，并提供了初步证据表明这种治疗可提高1年无截肢生存率。虽然这些结果是有希望的，但有机会通过鉴定更有效的祖细胞来源和评估移植细胞的功能特征来提高CLI细胞治疗的有效性。虽然许多基于心血管细胞的试验都集中在ABMNC上，但脂肪基质细胞（ASCs）已经证明了特别适合在CLI中促进保肢的品质。此外，脐带血单核细胞（CBMNC）已被证明包括血管生成内皮祖细胞，以增加缺血肢体的灌注，并被免疫活性宿主耐受。CLI提供了一个极好的机会来检查这两个容易获得的细胞群是否适合心血管细胞治疗，因为没有其他选择来挽救索引肢体，潜在的不良事件不会立即危及生命，并且在截肢的情况下可以获得组织用于分析。另外，CLI中促进保肢的机制与心肌缺血综合征相关。在这个新的区域中心的申请中，我们提出了两个方案，分别评估同种异体脐带血单核细胞和脂肪基质细胞作为CLI的潜在疗法。目的1将评价CBMNC在促进Rutherford 4类严重肢体缺血受试者1年无截肢生存率方面是否上级安慰剂，并且标准血运重建无/高风险选择。目的2将检验以下假设：脂肪基质细胞（ASC）是安全的，可能会延长严重肢体缺血和溃疡/组织缺损受试者的截肢时间（Rutherford分类5-6）。

DESCRIPTION (provided by applicant): The Indiana Regional Cardiovascular Cell Therapy Center (IRCCTC) will extend the work of the Cardiovascular Cell Therapy Research Network, particularly in the area of peripheral arterial disease (PAD). Critical limb ischemia (CLI) results in at least 50,000 amputations annually, with a cost estimated at $4.3 billion/year. In a recent Phase l/ll trial we have demonstrated safety and feasibility of intra-muscular injection of autologous bone marrow mononuclear cells (ABMNC) in patients with CLI, and provided initial evidence that this treatment improves amputation-free survival at one year. Although these results are promising, there is an opportunity to improve the effectiveness of cell therapy for CLI by identifying more potent sources of progenitor cells and by evaluating functional characteristics of transplanted cells. While many cardiovascular cell-based trials have focused on ABMNC, adipose stromal cells (ASCs) have demonstrated qualities particularly suitable for promoting limb salvage in CLI. In addition, cord blood mononuclear cells (CBMNC) have been shown to include vasculogenic endothelial progenitor cells, to augment perfusion in ischemic limbs, and to be tolerated by an immunocompetent host. CLI presents an excellent opportunity to examine these two readily accessible cell populations with regard to suitability for cardiovascular cell therapy, in that there exist no other options fo salvage of the index limb, potential adverse events are not immediately life-threatening, and tissue can be obtained for analysis in the event of amputation. Also, mechanisms promoting limb salvage in CLI have relevance to myocardial ischemic syndromes. In this application for a new Regional Center, we propose two protocols, respectively evaluating allogeneic cord blood mononuclear cells and adipose stromal cells as potential therapies for CLI. Aim 1 will evaluate whether CBMNC are superior to placebo in promoting amputation-free survival at 1 year in subjects with critical limb ischemia of Rutherford Category 4, and no /high-risk options for standard revascularization. Aim 2 will test the hypothesis that adipose stromal cells (ASCs) are safe and may increase time to amputation in subjects with critical limb ischemia and ulcers / tissue loss (Rutherford Category 5-6).