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

描述（由申请人提供）：R43 SBIR：用于药物开发的iPSC衍生人血管系统的开发。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，并在基因定义的亚群和血管罕见疾病患者（如马凡氏综合征）中开发药物方面具有巨大的潜力，iPSC可以从中获得。然而，尚未明确证明iEC和iSMC与分化的人原代成体血管细胞在表型上相似，包括疾病风险 因子和药物反应性。这不能被低估，因为最近对iPSC衍生的肝细胞的研究已经表明，这些细胞为FDA和制药行业提供有限的药物发现效用，因为它们保留了许多“胎儿”样特征，不能表达许多细胞色素p450酶的原代肝细胞水平，包括CYP3A家族，其负责代谢人体中超过60%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体原代细胞的体内生物学。在该系统中，血管内皮细胞从非生理“状态”中被拯救出来，如通过恢复体内区域特异性 形态学、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、血栓形成和炎症风险因素的反应接近人体体内暴露水平，通常与标准2D静态系统相差1至2个数量级。本SBIR的目的是确定HemoShear Vascular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，为遗传定义的血管疾病中急需的药物开发平台创建框架。

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.