Development of an iPSC-derived human hepatocyte platform for drug development.

描述(申请人提供)：人可诱导多能干细胞(IPSCs)容易增殖，并可向肝细胞终末分化，这使它们与原代人类肝细胞相比具有潜在的吸引力和成本效益。此外，将平台标准化到单个人类供体或可能包含已知遗传药物代谢多态(S)的供体(S)的能力，可以消除或极大地降低与原代肝细胞相关的供体-供体变异性。不幸的是，已经清楚地证明了分化的IPSC来源的肝细胞(IHC)，尽管在许多方面与原代肝细胞相似，但保留了某些类似于胎儿的方面。这包括胎儿类蛋白的表达增加，例如胎儿蛋白，以及特定细胞色素P450酶活性的降低，例如负责代谢60%以上药物的细胞色素P450家族。因此，制药业和监管机构认为IHC的使用前景看好，但目前存在局限性。在新的肝细胞平台上“成熟”这些细胞的尝试并未被证明是成功的。HemoSher是一家生物技术研究公司，利用专利方法在体外恢复对人类原代细胞的活体反应。我们商业化了一种人类原代肝细胞平台，该平台结合了受控血流动力学和运输的生理学原理，以恢复和保持成熟的、体内类似的分化表型、形态和代谢功能。该平台中的肝细胞对体内浓度的药物和激素做出反应。这项快速通道SBIR的目的是开发一个使用HemoSher技术的IHC平台，在生理水平上成熟IHC差异化功能和药物反应，为将急需的药物安全性和有效性评估平台商业化提供框架。

DESCRIPTION (provided by applicant): Human inducible pluripotent stem cells (iPSCs) proliferate readily and can be terminally differentiated into hepatocytes, which potentially makes them an attractive, cost-effective resource compared to primary human hepatocytes. Moreover, the ability to standardize a platform to a single human donor, or donor(s) who may include known genetic drug metabolism polymorphism(s), can eliminate or greatly reduce donor-donor variability associated with primary hepatocytes. Unfortunately, it has been clearly demonstrated that differentiated iPSC-derived hepatocytes (iHCs), though similar to primary hepatocytes in many ways, retain certain "fetal"-like aspects. This includes increased expression of fetal-like proteins, e.g.??fetal protein, and decreased activity of specific cytochrome p450 enzymes, e.g. the CYP3A family, which is responsible for metabolizing over 60% of drugs. Thus, the pharmaceutical industry and regulatory agencies view the use of iHCs as promising but currently limited. Attempts to "mature" these cells in novel hepatocyte platforms have not proven successful. HemoShear is a biotechnology research company that utilizes patented methodologies to restore in vivo responsiveness to human primary cells in vitro. We commercialized a human primary hepatocyte platform that combines physiological principles of controlled hemodynamics and transport to restore and maintain mature, in vivo-like differentiated phenotype, morphology and metabolic function. Hepatocytes in this platform respond to drugs and hormones at in vivo concentrations. The purpose of this Fast-Track SBIR is to develop an iHC platform using the HemoShear technology to mature iHC differentiated function and drug responses at physiological levels, providing the framework for commercializing a much needed platform for drug safety and efficacy assessment.