In vivo expansion of human hepatocytes in Fah-/-Rag-/-Il2rg-/- mice

Fah-/-Rag-/-Il2rg-/- 小鼠体内人肝细胞的扩增

• 批准号: 7805470
• 负责人: Markus Grompe
• 金额: $ 32.55万
• 依托单位: YECURIS CORPORATION
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-15 至 2011-04-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7805470
• 关键词: Animal Model; Biological Models; Data; Dichloromethylene Diphosphonate; Dose; Drug Kinetics; Goals; Hepatic; Hepatocyte; Human; Individual; Kupffer Cells; Liposomes; Liver; Metabolic; Metabolism; Mouse Strains; Mus; Mutant Strains Mice; Pharmacologic Substance; Phase; Phase I Clinical Trials; Production; Public Health; Regimen; Side; Site; Small Business Technology Transfer Research; Staging; System; Technology; Testing; Transplantation; Xenobiotic Metabolism; commercialization; cost; drug development; drug metabolism; gadolinium chloride; genetic selection; human subject; in vivo; irradiation; liver transplantation; macrophage; novel; public health relevance; small molecule

DESCRIPTION (provided by applicant): The liver is the site of many metabolic processes, including metabolism of xenobiotics such as pharmaceutical compounds. Drug metabolism is highly species specific and can vary significantly between individuals of the same species. To date no reliable experimental system capable of predicting the human-specific metabolic conversion of candidate small molecules exists. Our company (Yecuris Inc.) has developed an in vivo genetic selection system (the FRG mouse) that permits extensive humanization of murine liver by transplanted human hepatocytes. Preliminary data show that highly humanized mice (>80%) accurately reflect most aspects of human drug metabolism. Therefore highly humanized FRG mice are an attractive novel system for modeling human drug metabolism and pharmacokinetics at an early stage of drug development. However, the extent of liver humanization achieved in our mice currently remains highly variable, ranging from <5% to >90%. In order to make our platform more attractive to commercial customers and more commercially viable (reduced production cost per mouse), it will be necessary to reproducibly achieve high humanization levels in the majority of mice. In this phase 1 STTR application we propose 2 specific aims to advance our goal of reliable liver humanization: 1) We will test different background strains of mice for their ability to support high level liver repopulation. 2) The effects of different regimens to deplete/inhibit hepatic Kupffer cells on repopulation levels will be ascertained. PUBLIC HEALTH RELEVANCE: The animal model is an attractive novel system for modeling human drug metabolism and pharmacokinetics at an early stage of drug development. Commercialization of our technology will greatly reduce the cost of and accelerate new drug development, thus contributing to public health.

描述（由申请人提供）：肝脏是许多代谢过程的部位，包括外源性物质（如药物化合物）的代谢。药物代谢是高度物种特异性的，并且在相同物种的个体之间可以显著变化。迄今为止，还没有可靠的实验系统能够预测候选小分子的人类特异性代谢转化。本公司（Yecuris Inc.）已经开发了一种体内遗传选择系统（FRG小鼠），其允许通过移植的人肝细胞对鼠肝进行广泛的人源化。初步数据显示，高度人源化的小鼠（>80%）准确地反映了人类药物代谢的大部分方面。因此，高度人源化的FRG小鼠是在药物开发的早期阶段用于模拟人类药物代谢和药代动力学的有吸引力的新系统。然而，目前在我们的小鼠中实现的肝脏人源化程度仍然高度可变，范围为<5% to >90%。为了使我们的平台对商业客户更具吸引力，并且更具商业可行性（降低每只小鼠的生产成本），有必要在大多数小鼠中可重复地实现高人源化水平。在这个1期STTR申请中，我们提出了2个具体目标，以推进我们可靠的肝脏人源化目标：1）我们将测试不同背景品系的小鼠支持高水平肝脏再增殖的能力。2)将确定消耗/抑制肝枯否细胞的不同方案对再增殖水平的影响。 公共卫生相关性：动物模型是在药物开发的早期阶段用于模拟人类药物代谢和药代动力学的有吸引力的新系统。我们技术的商业化将大大降低新药开发的成本，加快新药开发的速度，从而为公众健康做出贡献。