Human iPSC-derived endothelial cells as Vascular Therapeutics

人 iPSC 衍生的内皮细胞作为血管治疗药物

• 批准号: 10505267
• 负责人: Young-Sup Yoon
• 金额: $ 54.6万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-15 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10505267
• 关键词: Age; Age-Years; Allogenic; Amputation; Animal Model; Applications Grants; Area; Autologous; Biological; Biological Assay; Biological Products; Blood Vessels; Bone Marrow; Cell Culture System; Cell Differentiation process; Cell Therapy; Cells; Characteristics; Clinical; Clinical Paths; Clinical Trials; Dependence; Development; Diabetic Neuropathies; Diabetic Retinopathy; Disease; Endothelial Cells; Engraftment; Ensure; Ethical Issues; Evaluation Research; Flow Cytometry; Future; Gene Expression; Generations; Germ Cells; Goals; Grant; Health; Hindlimb; Human; Immune; In Vitro; Intermittent Claudication; Intervention; Ischemia; Karyotype determination procedure; Lead; Limb Salvage; Long-Term Effects; Measurement; Mesenchymal Stem Cells; Molecular; Mononuclear; Myocardial Ischemia; Operative Surgical Procedures; Outcome; Pain; Patients; Peripheral Blood Stem Cell; Peripheral arterial disease; Phase; Plasmids; Population; Procedures; Property; Protocols documentation; Public Health; Recovery; Research Personnel; Rest; Safety; Source; Standardization; Stroke; System; Technology; Teratoma; Testing; Therapeutic; Therapeutic Agents; Therapeutic Effect; Ulcer; Validation; Vascular blood supply; Vascular regeneration; Virus; Work; adult stem cell; bench to bedside; bioluminescence imaging; critical limb Ischemia; design; effective therapy; endothelial stem cell; expectation; experience; healthy volunteer; human embryonic stem cell; human pluripotent stem cell; immunoreaction; in vivo; induced pluripotent stem cell; microCT; multimodality; optimal treatments; paracrine; peripheral blood; pluripotency factor; preclinical study; protein expression; regenerative; sex; stem cells; vector; volunteer; wound healing

Project Summary Peripheral arterial disease (PAD) afflicts approximately 15% of the U.S. population over 55 years of age. Initially characterized by intermittent claudication, progressive PAD results in unrelenting rest pain and ulceration, a condition referred to as critical limb ischemia (CLI). Despite advances in percutaneous intervention or surgical treatment, up to half of these CLI patients are amputated within one year. Pathophysiologically, alleviation of ischemia through direct vessel formation would be an optimal treatment. While cell therapy with adult stem or progenitor cells has been investigated as a new revascularization therapy for PAD, clinical trials showed no or minimal effects. Meanwhile, human induced pluripotent stem cells (hiPSCs) were discovered and showed almost similar properties to human embryonic stem cells (hESCs). Because of genuine differentiation capacity to target cells, hiPSCs have emerged as a promising therapeutic option for cell therapy. We and others developed a protocol to generate hiPSCs with non-integrating episomal vectors from a small amount of peripheral blood. We further developed a system to differentiate hiPSCs into endothelial cells (hiPSC-ECs) in a clinically compatible manner and demonstrated their long-term vessel-forming effects and therapeutic effects on animal models. The ultimate goal of this project is to develop hiPSC-ECs as a therapeutic agent for treating severe peripheral artery disease. Specifically, in this proposal, we will generate hiPSCs from peripheral blood of PAD patients and normal volunteers, differentiate them into hiPSC-ECs using our established procedure. We will then determine the identity and potency of these hiPSC- ECs using both in vitro and in vivo assays, particularly focusing on whether there is similar potency between the patient-derived and normal-volunteer-derived hiPSC-ECs. If shown similarity, a safer autologous approach will be developed for this disease. Despite its incredible therapeutic potential, cell therapy with hiPSC-ECs was not published or proposed worldwide to date. Our team of investigators have all the necessary expertise and experience to move our discovery into a future clinical trial. This grant will bridge the utility of hiPSCs from bench to bedside, which, we believe, will be the most significant source of cell therapy in the near future. Moreover, this work is a first step for therapeutic application of hiPSC- EC. There are many potential diseases that need a vascular supply such as ischemic heart disease, stroke, diabetic retinopathy, diabetic neuropathy, and wound healing, which will be all candidates that benefit from this development. Thus, the impact of this study will be huge.

项目摘要 外围动脉疾病（PAD）在55年内遭受了约15％的美国人口 年龄。最初以间歇性lau不平为特征 休息疼痛和溃疡，这种疾病称为临界肢体缺血（CLI）。尽管进步 在经皮干预或手术治疗中，最多一半的CLI患者被截肢 一年之内。病理生理，通过直接血管形成减轻缺血 将是一种最佳治疗方法。而成人茎或祖细胞的细胞疗法一直是 临床试验被调查为一种新的血运重建疗法，显示没有或最少 效果。同时，发现了人类诱导的多能干细胞（HIPSC）并显示 与人类胚胎干细胞（HESC）几乎相似。因为真实 靶细胞的分化能力，HIPSC已成为有前途的治疗选择 用于细胞疗法。我们和其他人开发了一种协议来生成具有非整合的HIPSC 来自少量外周血的偶发向量。我们进一步开发了一个系统 以临床兼容的方式将hipsc分为内皮细胞（HIPSC-EC） 证明了它们的长期血管形成作用和对动物模型的治疗作用。 该项目的最终目标是开发HIPSC-ECs作为治疗剂 治疗严重的外周动脉疾病。具体来说，在此提案中，我们将生成HIPSCS 从PAD患者和正常志愿者的外围血液中，将他们区分为HIPSC-EC 使用我们既定的程序。然后，我们将确定这些hipsc-的身份和效力 EC都使用体外和体内测定，特别是关注是否有类似的效力 在患者衍生和正常志愿者衍生的HIPSC-EC之间。如果显示出相似性，则更安全 该疾病将开发自体方法。 尽管具有令人难以置信的治疗潜力，但使用HIPSC-EC的细胞疗法并未发表 或迄今为止在全球范围内提议的。我们的调查人员团队拥有所有必要的专业知识， 将我们的发现转移到以后的临床试验中的经验。这笔赠款将桥接 从长凳到床边的HIPSC，我们认为这将是最重要的细胞来源 在不久的将来的治疗。此外，这项工作是用于治疗应用HIPSC-的第一步。 EC。有许多潜在疾病需要血管供应，例如缺血性心脏 疾病，中风，糖尿病性视网膜病，糖尿病神经病和伤口愈合，这将全部 从这一发展中受益的候选人。因此，这项研究的影响将是巨大的。