Chimeric Mice: Improving Drug Safety

嵌合小鼠：提高药物安全性

• 批准号: 9332249
• 负责人: GARY A PELTZ
• 金额: $ 63.14万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-15 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9332249
• 关键词: Acute Liver Failure; Animals; Characteristics; Drug Approval; Drug toxicity; Engineering; Ensure; Gene Expression; Genes; Genome engineering; Hepatocyte; Hepatotoxicity; Human; Liver; Methodology; Methods; Modeling; Molecular Target; Mus; Organ; Pathway interactions; Performance; Pharmaceutical Preparations; Phase; Predisposition; Process; Public Health; Residual state; Rodent; Safety; Series; Testing; Toxic effect; Toxicology; Tyrosine Kinase Inhibitor; bosentan; drug metabolism; drug testing; fialuridine; human subject; humanized mouse; improved; liver injury; mouse genome; next generation; nucleoside analog; programs; response

Abstract Drug-induced liver injury (DILI) has become a leading cause of acute liver failure, and it is the most common reason for regulatory actions after drug approval. Differences in the drug metabolism and drug disposition pathways used by humans and animal species have limited the predictive utility of animal toxicology studies. Drugs that produced minimal or no toxicity in animal studies have sometimes caused significant DILI in humans. Given the significant public health problem caused by DILI, and the difficulties associated with regulatory actions occurring after drug approval, there is a critical need for better methods to identify candidate medications that will cause DILI. This program will use 21st century genome engineering and a liver humanization model to improve drug safety. Since liver is the target organ for many drug-induced toxicities, toxicology studies using mice with `humanized' livers should improve the safety of drugs that will be tested in human subjects. Analyses of their response to fialuridine and bosentan treatment have indicated that TK-NOG mice with humanized livers could identify drugs that will cause human-specific liver toxicity. However, for this model to achieve its potential, its performance must be assessed with a larger number of drugs with different hepatotoxic potential in rodents and humans. Therefore, we will evaluate the response of control and humanized TK-NOG mice to 7 selected drugs, which include: (i) 3 nucleoside analogues (two were safe for humans and one caused human-specific liver toxicity); (ii) two drugs with the same molecular target to determine if chimeric mice can distinguish between drugs that will or will not cause human-specific liver toxicity; and (iii) two tyrosine kinase inhibitors that were hepatotoxic in rodents but not in humans to determine whether this platform can identify drugs that will be safe for humans, even though they caused rodent-specific toxicities. We have shown that bosentan-induced cholestatic liver toxicity (BICLT) develops in humanized (but not control) TK-NOG mice. However, we do not know why humanized mice have increased susceptibility to BICLT. Therefore, a series of mechanistic studies will be performed to determine why humanized mice are selectively susceptible to this toxicity. Lastly, residual murine hepatocytes in the chimeric liver produce mouse-specific drug metabolites, which can confound the results of toxicology studies that use humanized TK-NOG mice. To produce a liver humanization platform with better performance characteristics, mouse genome engineering will be used to inactivate key murine genes involved in phase I drug metabolism. A two-stage process will be used to ensure that murine phase I drug metabolism has been optimally reduced in these mice. Their response to 6 different drugs, which have different hepatotoxic potential in rodents and humans, will be assessed to determine if this next generation platform can better predict the human hepatotoxic potential of candidate medications.

抽象的 药物性肝损伤（DILI）已成为急性肝衰竭的主要原因，也是最常见的 药品批准后采取监管行动的原因。药物代谢和药物处置的差异 人类和动物物种使用的途径限制了动物毒理学研究的预测效用。 在动物研究中产生最小毒性或无毒性的药物有时会导致严重的 DILI 人类。鉴于 DILI 造成的重大公共卫生问题以及与之相关的困难 药物批准后发生监管行动，迫切需要更好的方法来识别候选药物 会导致 DILI 的药物。该计划将使用 21 世纪的基因组工程和肝脏 提高用药安全性的人性化模型。 由于肝脏是许多药物引起的毒性的靶器官，因此使用“人源化”小鼠进行毒理学研究 肝脏应该提高将在人类受试者中测试的药物的安全性。分析他们的反应 非阿尿苷和波生坦治疗表明具有人源化肝脏的 TK-NOG 小鼠可以识别药物 会引起人类特有的肝脏毒性。然而，要使该模型发挥其潜力，其性能 必须用大量对啮齿动物和人类具有不同肝毒性潜力的药物进行评估。 因此，我们将评估对照小鼠和人源化 TK-NOG 小鼠对 7 种选定药物的反应，其中 包括： (i) 3 种核苷类似物（其中两种对人类安全，一种引起人类特异性肝毒性）； (ii) 具有相同分子靶标的两种药物，以确定嵌合小鼠是否能够区分 会或不会引起人类特异性肝毒性； (iii) 两种具有肝毒性的酪氨酸激酶抑制剂 啮齿动物而不是人类，以确定该平台是否可以识别对人类安全的药物， 尽管它们会引起啮齿类动物特有的毒性。我们已经证明波生坦诱导的胆汁淤积性肝 人源化（而非对照）TK-NOG 小鼠中出现毒性（BICLT）。然而，我们不知道为什么 人源化小鼠对 BICLT 的易感性增加。因此，一系列的机理研究将 目的是确定为什么人源化小鼠选择性地对这种毒性敏感。最后，残留的鼠类 嵌合肝脏中的肝细胞产生小鼠特异性药物代谢物，这可能会混淆以下结果： 使用人源化 TK-NOG 小鼠进行毒理学研究。打造更好的肝脏人源化平台 性能特征，小鼠基因组工程将用于灭活涉及的关键小鼠基因 处于 I 期药物代谢。将使用两阶段过程来确保小鼠 I 期药物代谢 在这些小鼠中已得到最佳减少。他们对 6 种不同药物的反应，这些药物具有不同的肝毒性 将评估啮齿动物和人类的潜力，以确定下一代平台是否可以更好 预测候选药物的人类肝毒性潜力。