Humanized Chimeric Rodent Models
Current pre-clinical animal models have been- useful to study the many aspects of mammalian biological systems, however translating discoveries in rodents into clinical applications often falls short due to species related differences in biology, drug ADME (absorption, distribution, metabolism, and excretion), and toxicity, leading to the failure of drug candidates. In order to overcome these limitations “humanized” rodent models haven been developed and they are becoming a crucial tool for researchers, toxicologists, and pharmacologists which provides confidence in their ADME-Tox findings, drug safety assessments and may prevent drug failures.
There are two approaches for creating humanized models; tissue or cellular humanization and genetic humanization. Tissue or cellular humanization involves replacing cells or entire organs with human cells in order to develop a functioning human liver or immune system within the model organism. Genetic humanization uses genetic modification to replace a particular endogenous gene or genes, such as the Cyp2d, which are is involved in drug metabolism, with their human orthologs.
Studies and Applications
- Repopulation of the immunosuppressed retrorsine-treated infant rat liver with human hepatocytes
Summary: Mice with livers mostly replaced by human hepatocytes have been proven to be useful for research on drug metabolism and toxicity and on intrahepatic pathogens such as hepatitis. However, their small body size prohibits collecting sufficient biological samples and made surgical manipulation difficult. It is for these reasons that the authors developed the rat humanized liver model. The rat also provides the benefit of having abundant pharmacological data which has been accumulated in studies with rats, because they have been traditionally and commonly used in the pre-clinical development of new drugs. One limitation of this rat model is it requires chemical immunosuppression, this can be improved by the creation of a genetically modified rat strain that is fully immunodeficient.
Tachibana, et al. Xenotransplantation 2013 August. 20: 227–238.
- Chimeric mice transplanted with human hepatocytes as a model for prediction of human drug metabolism and pharmacokinetics
Abstract: Preclinical studies in animal models are used routinely during drug development, but species differences of pharmacokinetics (PK) between animals and humans have to be taken into account in interpreting the results. Human hepatocytes are also widely used to examine metabolic activities mediated by cytochrome P450 and other enzymes, but such in vitro metabolic studies also have limitations. Recently, chimeric mice with humanized liver, generated by transplantation of human donor hepatocytes, have been developed as a model for the prediction of metabolism and PK in humans, using both in vitro and in vivo approaches. The expression of human-specific metabolic enzymes and metabolic activities was confirmed in humanized liver of chimeric mice with high replacement ratios, and several reports indicate that the profiles of P450 and non-P450 metabolism in these mice adequately reflect those in humans. Further, the combined use of human chimeric mice and rat chimeric mice, in which endogenous hepatocytes are replaced with rat hepatocytes, is a promising approach for evaluation of species differences in drug metabolism. Recent work has shown that data obtained in h-chimeric mice enable the semi-quantitative prediction of not only metabolites, but also PK parameters, such as hepatic clearance, of drug candidates in humans, although some limitations remain because of differences in the metabolic activities, hepatic blood flow and liver structure between humans and mice. In addition, fresh human hepatocytes can be isolated reproducibly from chimeric mice for metabolic studies.
Sanoh, et al. Biopharmaceutics & Drug Disposition. 2014 March. 35-2; 71–86.
- Fialuridine Induces Acute Liver Failure in Chimeric TK-NOG Mice: A Model for Detecting Hepatic Drug Toxicity Prior to Human Testing
Summary: Several clinical trial participants treated with a nucleoside analogue (fialuridine [FIAU]) developed acute liver failure resulting in the death of 5 participants, and 2 required a liver transplant. Preclinical toxicology studies in mice, rats, dogs, and primates did not provide any indication that FIAU would be hepatotoxic in humans. Therefore, it was investigated whether FIAU-induced liver toxicity could be detected in chimeric TK-NOG mice with humanized livers. Toxicity could be readily detected using chimeric TK-NOG mice with humanized livers, even when the mice were treated with a FIAU dose that was only 10-fold above the dose used in human participants and changes observed in FIAU-treated chimeric mice mirrored those of FIAU-treated human participants. The use of chimeric mice in preclinical toxicology studies could improve the safety of candidate medications selected for testing in human participants.
Xu, et al. PLoS Medicine. 2014 April. 11(4): e1001628.