PLOS Medicine Associate Editor Laureen Connell discusses a research article from 2014 in which Gary Peltz and colleagues described a new mouse model with a humanized liver that can replicate human-specific toxicity and improve safety of clinical trials.
In 1993, fialuridine (a nucleoside analogue used to treat hepatitis B virus infection) was tested in humans in a phase II trial after earlier preclinical testing in animals suggested the drug was safe. Some participants had a variety of severe reactions to the drug, including liver failure, lactic acidosis, and steatosis, which led to the death of five participants. Human-specific drug toxicity is a potential problem that requires screening early in drug development. The development of accurate models in the lab to test drugs for toxicity before serious side effects arise during clinical trials in humans is an important part of developing therapeutics. Also, more nucleoside analogues are being developed as therapeutics, and therefore improved screening tools are needed for human-specific toxicity. Peltz and colleagues recently explored this problem when they investigated whether testing fialuridine in a new mouse model would have predicted the problems found in humans during clinical trials.
Chimeric TK-NOG mice with humanized livers were generated in 2011 and have been used to predict human-specific drug metabolism and interactions with other drugs. These chimeric TK-NOG mice have been transplanted with human liver cells in order to establish a long-lived mature “human organ.” Previous mouse models used for testing drug toxicity in humans had many limitations and did not accurately predict toxicity in humans. The TK-NOG chimeric mouse was generated by expressing a herpes simplex virus type 1 thymidine kinase (TK) transgene within the liver of a highly immunodeficient mouse strain (NOG). The mouse’s liver cells expressing the transgene were ablated by exposure to an antiviral drug, allowing transplanted human liver cells to develop into a humanized liver, with a three-dimensional architecture and gene expression pattern characteristic of mature human liver and containing only a small percentage of mouse liver cells.