Humanized Liver Mouse Model to Boost Hepatitis Drug Development

A recent paper described the creation of a mouse model system for the study of liver diseases such as hepatitis that should become an important tool for the development of antiviral drugs.

Together, hepatitis C virus (HCV) and hepatitis B virus (HBV) chronically infect more than 500 million people worldwide and account for about two-thirds of all liver cancers, the third most common cause of cancer-related death. Historically, studying the life cycles of these viruses and the development of the corresponding antiviral drugs has been hampered by the lack of small animal models for both pathogens. While chimpanzees are susceptible to hepatitis, their usage is limited for ethical and practical reasons.

In the current study, investigators from the Salk Institute for Biological Studies (La Jolla, CA, USA) sought to improve on a mouse model that housed a partially "humanized” liver. To this end, they replaced the previously used mouse strain with a different, immunodeficient, but otherwise healthy mouse strain that could be engrafted with human hepatocytes readily and reproducibly, irrespective of the age of the mouse.

In this mouse strain, the selection pressure for transplanted hepatocytes was accentuated due to absence of the enzyme fumaryl acetoacetate hydrolase (FAH). Lack of this enzyme leads to an accumulation of toxic tyrosine catabolites within mouse hepatocytes. This genetically determined toxicity is preventable by oral administration of 2-(2-nitro-4-trifluoro-methylbenzoyl)-1,3-cyclohexanedione (NTBC), which blocks hydroxyphenylpyruvate dioxygenase activity upstream of FAH and therefore prevents the accumulation of toxic metabolites in the liver cells.

Results of the study published in the February 22, 2010, online edition of the Journal of Clinical Investigation revealed that the livers of these immunodeficient mice could be very efficiently repopulated by human hepatocytes after withdrawal of NTBC, and then infected by HBV and HCV. Furthermore, the "humanized” HCV-infected livers inside the mice responded similarly to human livers when treated with pegylated interferon alpha 2a, the standard treatment for hepatitis C.

"Human hepatocytes are almost impossible to work with, as they do not grow and are hard to maintain in culture,” explained senior author Dr. Inder Verma, professor of genetics at the Salk Institute. "This robust model system opens the door to utilize human hepatocytes for purposes that were previously impossible. This chimeric mouse can be used for drug testing and gene therapy purposes, and in the future, may also be used to study liver cancers.”

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Salk Institute for Biological Studies