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.

项目概要 55 年来，约 15% 的美国人患有外周动脉疾病 (PAD) 的年龄。最初以间歇性跛行为特征，进行性 PAD 导致无情的症状 静息痛和溃疡，这种情况称为严重肢体缺血 (CLI)。尽管取得了进步 在经皮介入或手术治疗中，多达一半的 CLI 患者需要截肢 一年内。病理生理学上，通过直接血管形成缓解缺血 将是一个最佳的治疗方法。虽然使用成体干细胞或祖细胞的细胞疗法已 作为一种新的 PAD 血运重建疗法进行研究，临床试验显示没有或很少 影响。与此同时，人类诱导多能干细胞（hiPSC）被发现并显示 与人类胚胎干细胞（hESC）几乎相似的特性。因为正品 hiPSC 具有向靶细胞分化的能力，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协议来生成具有非整合性的 hiPSC 来自少量外周血的附加型载体。我们进一步开发了一个系统 以临床兼容的方式将 hiPSC 分化为内皮细胞 (hiPSC-EC) 证明了它们对动物模型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。具体来说，在本提案中，我们将生成 hiPSC 从 PAD 患者和正常志愿者的外周血中，将其分化为 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 使用体外和体内测定，特别关注是否有相似的效力 患者来源的 hiPSC-EC 和正常志愿者来源的 hiPSC-EC 之间的差异。如果表现出相似性，则更安全 将为这种疾病开发自体方法。 尽管 hiPSC-EC 的细胞疗法具有令人难以置信的治疗潜力，但尚未发表 或迄今为止在全球范围内提出的建议。我们的研究团队拥有所有必要的专业知识和 经验将我们的发现转移到未来的临床试验中。这笔赠款将弥合效用 hiPSC 从实验室到临床，我们相信这将是最重要的细胞来源 在不久的将来进行治疗。此外，这项工作是 hiPSC-治疗应用的第一步 欧共体。有许多潜在的疾病需要血管供应，例如缺血性心脏 疾病、中风、糖尿病视网膜病变、糖尿病神经病变和伤口愈合，这些都将是 受益于这一发展的候选人。因此，这项研究的影响将是巨大的。