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

描述（由申请人提供）：肝脏是许多代谢过程的场所，包括药物化合物等异种生物的代谢。药物代谢具有高度的物种特异性，在同一物种的个体之间可能存在显著差异。到目前为止，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。我们的公司（Yecuris Inc.）开发了一种体内遗传选择系统（FRG小鼠），该系统允许通过移植的人类肝细胞对小鼠肝脏进行广泛的人源化。初步数据显示，高度人源化小鼠（bbb80 %）准确反映了人类药物代谢的大多数方面。因此，高度人源化的FRG小鼠是在药物开发早期模拟人类药物代谢和药代动力学的一个有吸引力的新系统。然而，在我们的小鼠中实现的肝脏人源化程度目前仍然高度可变，从<5%到bb0 - 90%不等。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重复地实现高人源化水平。在这个第一阶段的STTR应用中，我们提出了两个具体的目标来推进我们可靠的肝脏人源化的目标：1)我们将测试不同背景的小鼠株支持高水平肝脏再生的能力。2)将确定不同消耗/抑制方案对肝库普弗细胞再生水平的影响。

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.