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: 10054574
• 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 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10054574
• 关键词: Age; Age-Years; Allogenic; Amputation; Animal Model; Applications Grants; Area; Autologous; Biological; Biological Assay; 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; Natural regeneration; 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; 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; 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 外周动脉疾病（PAD）在55年内折磨着大约15%的美国人口 年龄。最初以间歇性跛行为特征，进行性PAD导致持续的 静息痛和溃疡，一种被称为严重肢体缺血（CLI）的病症。尽管取得了进展 在经皮介入或手术治疗中，多达一半的CLI患者被截肢 一年内病理生理学上，通过直接血管形成缓解缺血 会是最佳的治疗方法虽然使用成体干细胞或祖细胞的细胞疗法已经被广泛应用， 作为一种新的PAD血运重建疗法，临床试验显示， 方面的影响.与此同时，人类诱导多能干细胞（hiPSCs）被发现并显示， 与人类胚胎干细胞（hESC）几乎相似的特性。因为真正的 由于hiPSC具有向靶细胞分化的能力，因此已成为一种有前途的治疗选择， 用于细胞治疗我们和其他人开发了一种方案来产生具有非整合的hiPSC。 来自少量外周血的游离型载体。我们进一步开发了一个系统， 以临床相容的方式将hiPSC分化为内皮细胞（hiPSC-EC）， 在动物模型上证明了它们的长期血管形成作用和治疗作用。 该项目的最终目标是开发hiPSC-EC作为治疗剂， 治疗严重的外周动脉疾病具体而言，在本提案中，我们将生成hiPSC 从PAD患者和正常志愿者外周血中分离hiPSC-EC， 用我们既定的程序我们将确定这些hiPSC的身份和效力- 使用体外和体内测定的EC，特别关注是否具有相似的效力 患者来源和正常志愿者来源的hiPSC-EC之间的差异。如果有相似之处， 将发展自体方法治疗这种疾病。 尽管hiPSC-EC具有令人难以置信的治疗潜力，但其细胞疗法尚未发表 或迄今为止在全球范围内提出的。我们的调查团队拥有所有必要的专业知识， 将我们的发现用于未来的临床试验。这笔赠款将弥补 hiPSC从实验室到床边，我们相信，这将是最重要的细胞来源， 治疗在不久的将来。此外，这项工作是hiPSC治疗应用的第一步。 EC.有许多潜在的疾病，需要血管供应，如缺血性心脏病 疾病，中风，糖尿病视网膜病变，糖尿病神经病变和伤口愈合，这将是所有 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。