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

开发用于药物开发的 iPSC 衍生人肝细胞平台。

• 批准号: 9103147
• 负责人: Brian Robert Wamhoff
• 金额: $ 56.33万
• 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: 2014-07-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9103147
• 关键词: Albumins; Benchmarking; Biological; Biological Products; Biological Transport; Biotechnology; Blood Circulation; CYP2D6 gene; CYP3A4 gene; Cell Culture Techniques; Cell Survival; Cells; Clinical; Culture Media; Cytochrome P450; Development; Differentiation Antigens; Drug Industry; End Point Assay; Enzymes; Family; Fetal Proteins; Formulation; Gene Expression; Genetic; Genetic Polymorphism; Health; Hepatocyte; Hormones; Human; Image; In Vitro; Industry; International; Legal patent; Letters; Literature; Liver; Measurement; Measures; Metabolic; Methodology; Methods; Morphology; Omeprazole; Performance; Pharmaceutical Preparations; Phase; Phenobarbital; Phenotype; Physiological; Plasma; Pluripotent Stem Cells; Proliferating; Property; Protein Analysis; Proteins; Publishing; Qualifying; RNA; Research; Resources; Risk; Running; Safety; Small Business Innovation Research Grant; System; Technology; Therapeutic; Toxic effect; Urea; cost effective; cytotoxicity; drug candidate; drug development; drug discovery; drug metabolism; fetal; gene panel; hemodynamics; in vivo; induced pluripotent stem cell; metabolic phenotype; novel; response; success

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.

描述（由申请人提供）：人诱导性多能干细胞（iPSC）易于增殖，并可终末分化为肝细胞，这可能使其成为与原代人肝细胞相比具有吸引力且具有成本效益的资源。此外，将平台标准化为单个人供体或可能包括已知遗传药物代谢多态性的供体的能力可以消除或大大减少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，分化的iPSC衍生的肝细胞（iHC）尽管在许多方面类似于原代肝细胞，但保留了某些“胎儿”样方面。这包括胎儿样蛋白的表达增加，例如？胎儿蛋白，以及特定细胞色素p450酶（例如CYP 3A家族）活性降低，该酶负责代谢超过60%的药物。因此，制药行业和监管机构认为iHC的使用是有前途的，但目前是有限的。在新的肝细胞平台中使这些细胞“成熟”的尝试尚未被证明是成功的。HemoShear是一家生物技术研究公司，利用专利方法在体外恢复人体原代细胞的体内反应性。我们商业化了一种人原代肝细胞平台，该平台结合了受控血流动力学和转运的生理学原理，以恢复和维持成熟的体内样分化表型、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有反应。本快速通道SBIR的目的是使用HemoShear技术开发iHC平台，以在生理水平上成熟iHC分化功能和药物反应，为药物安全性和有效性评估急需的商业化平台提供框架。