Development of an iPSC-derived human vascular system for drug discovery and devel

开发 iPSC 衍生的人体血管系统用于药物发现和开发

• 批准号: 8780984
• 负责人: Brian Robert Wamhoff
• 金额: $ 24.9万
• 依托单位: HEMOSHEAR THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-20 至 2015-09-19
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8780984
• 关键词: Adopted; Adult; Adverse effects; Biology; Biotechnology; Blood Vessels; Blood flow; CYP3A4 gene; Cardiovascular Diseases; Cardiovascular system; Cells; Characteristics; Clinical; Coculture Techniques; Common carotid artery; Cytochrome P450; Databases; Decision Making; Development; Differentiation Antigens; Disease; Drug Exposure; Drug Industry; Endothelial Cells; Enzymes; Exposure to; Family; Genetic; Hepatocyte; Human; In Vitro; Inflammation Mediators; Inflammatory; International; Legal patent; Letters; Maps; Marfan Syndrome; Methodology; Molecular; Morphology; Non-Steroidal Anti-Inflammatory Agents; Patients; Pharmaceutical Preparations; Phase; Phenotype; Pluripotent Stem Cells; Population; Provider; Rare Diseases; Relative (related person); Research; Resistance; Risk Factors; Safety; Small Business Innovation Research Grant; Smooth Muscle; Smooth Muscle Myocytes; System; TNF gene; Technology; Toxic effect; Vascular Diseases; Vascular System; carotid sinus; disorder risk; drug development; drug discovery; exposed human population; fetal; hemodynamics; in vivo; oxidized low density lipoprotein; programs; prospective; public health relevance; response; restoration; success; transcriptomics; vascular inflammation

DESCRIPTION (provided by applicant): R43 SBIR: Development of an iPSC-derived human vascular system for drug development. ABSTRACT Human inducible pluripotent stem cells (iPSCs) can be differentiated into vascular endothelial (iEC) and smooth muscle (iSMC) cells and hold immense potential for developing drugs in genetically defined subpopulations and for patients with vascular rare diseases, such as Marfan's syndrome, from which iPSCs can be acquired. However, it has not been clearly demonstrated that iECs and iSMCs are phenotypically similar to differentiated human primary adult vascular cells, including disease risk factor and drug responsiveness. This cannot be understated as recent studies with iPSC-derived hepatocytes have shown that these cells provide limited utility to the FDA and pharmaceutical industry for drug discovery as they retain many "fetal"-like characteristics, failin to express primary hepatocyte levels of many cytochrome p450 enzymes, including the CYP3A family, which is responsible for metabolizing over 60% of drugs in humans. HemoShear, LLC is a biotechnology research company that utilizes patented methodologies (US 7,811,782) to restore in vivo biology to human primary cells in co-culture in vitro. In this system, vascular cels are rescued from a non-physiological "state" as indicated by restoration of region-specific in vivo morphology, expression of mature differentiation markers and function. Importantly, cells respond to drugs and disease, thrombotic and inflammatory risk factors that approximate in vivo human exposure levels, which are often 1 to 2 orders of magnitude different from standard 2D static systems. The purpose of this SBIR is to determine whether iECs and iSMCs in the HemoShear Vascular system achieve in vivo-like responsiveness similar to human primary vascular cells for utility in safety and drug discovery development, creating the framework for a much needed platform for drug development in genetically defined vascular diseases.

描述（由申请人提供）： R43 SBIR：开发 iPSC 衍生的人类血管系统用于药物开发。摘要：人类诱导性多能干细胞 (iPSC) 可以分化为血管内皮 (iEC) 和平滑肌 (iSMC) 细胞，在基因定义的亚群中开发药物以及治疗血管罕见疾病（如马凡氏综合征）患者具有巨大潜力，可以从中获得 iPSC。然而，尚未明确证明 iEC 和 iSMC 在表型上与分化的人类原代成体血管细胞相似，包括疾病风险 因素和药物反应。这不能被低估，因为最近对 iPSC 衍生肝细胞的研究表明，这些细胞对 FDA 和制药行业的药物发现作用有限，因为它们保留了许多“胎儿”样特征，无法表达许多细胞色素 p450 酶的原代肝细胞水平，包括 CYP3A 家族，该家族负责代谢人类 60% 以上的药物。 HemoShear, LLC 是一家生物技术研究公司，利用专利方法（US 7,811,782）在体外共培养中恢复人类原代细胞的体内生物学。在该系统中，血管细胞从非生理“状态”中被拯救出来，如体内区域特异性恢复所示 形态、成熟分化标志物的表达和功能。重要的是，细胞对药物和疾病、血栓形成和炎症危险因素的反应接近人体体内暴露水平，通常与标准 2D 静态系统有 1 到 2 个数量级的差异。该 SBIR 的目的是确定 HemoShear 血管系统中的 iEC 和 iSMC 是否能够实现与人类原代血管细胞相似的体内反应性，以用于安全性和药物发现开发，从而为基因定义的血管疾病药物开发急需的平台创建框架。

项目成果

Exposure of Induced Pluripotent Stem Cell-Derived Vascular Endothelial and Smooth Muscle Cells in Coculture to Hemodynamics Induces Primary Vascular Cell-Like Phenotypes.

• DOI: 10.1002/sctm.17-0004
• 发表时间: 2017-08
• 期刊: Stem cells translational medicine
• 影响因子: 6
• 作者: Collado MS;Cole BK;Figler RA;Lawson M;Manka D;Simmers MB;Hoang S;Serrano F;Blackman BR;Sinha S;Wamhoff BR
• 通讯作者: Wamhoff BR