Therapeutic Angiogenesis by Universal Donor Endometrial Regenerative Cells

描述（由申请人提供）：通过通用供体子宫内膜再生细胞（ERC）的治疗性血管生成摘要所提出的研究旨在开发一种实用的、现成的、通用的供体细胞疗法，用于被称为“严重肢体缺血”（CLI）的晚期外周动脉疾病。CLI患者面临的主要问题是四肢缺乏适当的血液循环。虽然在这些患者中已经记录了基础水平的侧支血管形成，但在许多情况下，这不足以防止截肢。通过给予血管生成细胞因子来增强侧支血管形成过程的方法在临床上基本上失败[1-3]。对此的一种解释是，细胞因子施用是在非生理条件下进行的，无论是在顺序还是组合方面。一种更有治疗前景的方法是给予自体干细胞，其在似乎更生理的条件下分泌血管生成细胞因子。许多临床试验已经证明了使用骨髓和动员的外周血干细胞群的益处，在以下参考文献[4]中进行了综述。不幸的是，成人自体细胞显示出降低的血管生成能力，特别是在CLI患者中[5，6]。此外，由于存在合并症，从骨髓或外周血中收获干细胞的程序被认为对CLI患者是危险的[7，8]。从实践的角度来看，自体治疗只能在具有认证的洁净室和细胞处理经验的专业中心进行。Medistem，Inc.已经鉴定了一种称为“子宫内膜再生细胞”（ERC）的新型干细胞群，该公司正在与通用生物技术有限责任公司合作开发“通用供体”人群。到目前为止，这种合作已经产生了一种细胞群，该细胞群抑制炎症反应，不引起T细胞反应性，并且可以在体外和体内不存在免疫抑制的情况下在同种异体和异种宿主中存活。考虑到大量的血管生成生长因子分泌和刺激血管生成的能力，ERC可能是自体干细胞植入的商业上可行的替代品，其避免了以下问题：提取、年龄和疾病相关的干细胞功能障碍以及在护理点对洁净室设施的要求。目前的提案寻求支持，以扩大现有的疗效评价，以便进入Ib/II期临床试验。 公共卫生相关性：该项目旨在增加现有的安全性和生产数据，以提交Ib/II期IND，用于使用Medistem开发的称为子宫内膜再生细胞（ERC）的新型成体干细胞群治疗严重肢体缺血。现有的数据表明ERC具有有效的血管生成、抗炎作用，并且可以以“通用供体”的方式使用，从而为除了截肢之外缺乏治疗选择的病症提供了易于使用的现成细胞疗法。

DESCRIPTION (provided by applicant): Therapeutic Angiogenesis by Universal Donor Endometrial Regenerative Cells (ERC) Abstract The proposed study seeks to develop a practical, off the shelf, universal donor, cell therapy for an advanced form of peripheral artery disease termed "critical limb ischemia" (CLI). The major problem facing CLI patients is lack of proper circulation to the extremities. Although a basal level of collateral vessel formation has been documented in these patients, in many cases it is insufficient to prevent amputation. Methods of augmenting the process of collateral vessel formation through administration of angiogenic cytokines have largely failed clinically [1-3]. One explanation for this has been that cytokine administration was performed under conditions that were not physiological, both in terms of sequence and combinations. A more therapeutically promising method has been administration of autologous stem cells which secrete angiogenic cytokines under what appears to be more physiological conditions. Numerous clinical trials have demonstrated benefit using bone marrow and mobilized peripheral blood stem cell populations, which are reviewed in the following reference [4]. Unfortunately, adult autologous cells display reduced angiogenic capacity, especially in CLI patients [5, 6]. Additionally, the procedures for harvesting stem cells from the bone marrow or peripheral blood are considered to be dangerous in patients with CLI due to existing comorbidities [7, 8]. From a practical perspective autologous therapy can only be performed at specialized centers which have certified clean rooms and experience with cell processing. A novel stem cell population termed "endometrial regenerative cells" (ERC) has been identified by Medistem, Inc., that the company is developing with General BioTechnology, LLC as a "universal donor" population. To date this collaboration has resulted in a cell population that inhibits inflammatory responses, do not elicit T cell reactivity, and can survive in allogeneic and xenogeneic hosts in absence of immune suppression both in vitro and in vivo. Given the large amount of angiogenic growth factor secretion and ability to stimulate angiogenesis, the ERC may be a commercially viable substitute for autologous stem cell implantation that circumvents the problems of: extraction, age and disease associated stem cell dysfunction, and requirement for clean room facilities at the point of care. The current proposal seeks support to expand on existing efficacy evaluation so as to permit entry into Phase Ib/II clinical trials. PUBLIC HEALTH RELEVANCE: The project aims to augment existing safety and manufacturing data to submit a Phase Ib/II IND for treatment of critical limb ischemia using a novel adult stem cell population developed by Medistem termed Endometrial Regenerative Cells (ERC). Existing data demonstrates ERC are potently angiogenic, anti-inflammatory, and can be used in a "universal donor" manner, thus providing an easy to use, off the shelf cellular therapy for a condition that lacks therapeutic options besides amputation.