Chimeric rodents with humanized liver: bridging the preclinical/clinical trial gap in ADME/toxicity studies

Abstract

1. Immunocompromised mice with humanized livers were developed in the mid-1990s to allow the study of human hepatotropic viruses, which normally replicate only in higher primates. The production of the uPA/SCID mouse was the vanguard of these models and remains the most widely worked upon model for an ever increasing range of applications. 2. Since toxicology is conducted in laboratory animal species with the implicit intent of predicting the outcome of accidental, or intentional, human exposure, the potential for using an in vivo model with a humanised metabolism opens up the possibility of better predicting the human response following exposure to drugs and industrial chemicals. Chimeric humanised mice provide the tool for bridging between the non-clinical laboratory safety and metabolism studies, carried out in rodent and non-rodent species, and the first in man clinical trials. 3. Chimeric mice carrying a human liver have now been validated against a wide range of different drugs and chemical classes, and have been shown to clearly differentiate metabolically from the recipient mouse, and to show metabolic pathways more similar to those expected from human liver. 4. This review critically appraises the available animal models carrying human livers and where future developments would improve the existing systems.

Discovery and resupply of pharmacologically active plant-derived natural products: A review

“…In this context, an additional factor contributing to the broad use of rodents as first-line in vivo models for pharmacological testing is the availability and the established methods for de novo generation of genetically modified mice (with a gene-knockout, downregulation (knockdown), or overexpression of a protein of interest), as well as genetically modified rats, which are providing a set of additional approaches to study pharmacological effects. Such genetically modified rodent models are successfully applied for the verification of in vivo efficacy prior to human trials, for the discovery of new pharmacological targets, as well as to assist the elucidation of pharmacological mechanisms of action (Foster et al, 2014;Zambrowicz and Sands, 2003;Zhang et al, 2012). The generation of genetically modified animal models has dramatically evolved recently by the development of new TALEN-and CRISPR/Cas9-mediated techniques for genome editing Miller et al, 2011;Wang et al, 2013a).…”

“…Although such large animal models are associated with limitations, such as higher price and more pronounced ethical considerations, their use is still widely practiced, especially by the pharmaceutical industry, since the regulatory guidelines of FDA, European EMA, and other similar international and regional authorities usually require safety testing in at least two mammalian species, including one non-rodent species, prior to human trials authorization (Parasuraman, 2011;van der Laan et al, 2010). Indeed, rodent and human proteins are sometimes not similarly sensitive toward bioactive compounds (Huang et al, 2004;Kervinen et al, 2010), and therefore a higher confidence for safety and efficacy can be obtained by using several mammalian species, or genetically engineered "humanized" animal models if available (Foster et al, 2014;Scheer and Roland Wolf, 2013). In this context, an additional factor contributing to the broad use of rodents as first-line in vivo models for pharmacological testing is the availability and the established methods for de novo generation of genetically modified mice (with a gene-knockout, downregulation (knockdown), or overexpression of a protein of interest), as well as genetically modified rats, which are providing a set of additional approaches to study pharmacological effects.…”

Preventing Drug-Induced Liver Injury: How Useful Are Animal Models?

“…The combination of severe immunodeficiency defects in mice with a gene knockout or an expressed transgene causing damage to endogenous murine liver cells facilitates the engraftment and proliferation of transplanted human liver cells in the mouse liver [33]. The repopulated ‘humanized' liver contains both mouse and human hepatocytes in various proportions depending on the model considered.…”

“…Initially developed as models of HBV and HCV infection or Plasmodium falciparum infestation, this model has been used to study drug metabolism and, more recently, liver toxicity [33]. …”

Application of Chimeric Mice with Humanized Liver for Study of Human-Specific Drug Metabolism

“…Studies have demonstrated that uPA/SCID chimeric mice livers have expression levels and enzymatic activity for major human P450s and phase II conjugation enzymes similar to that in donor human hepatocytes (Katoh et al, 2004(Katoh et al, , 2005bTateno et al, 2004;Nishimura et al, 2005) and demonstrate a human-like susceptibility to CYP450 inhibition (Katoh et al, 2004(Katoh et al, , 2007 and induction (Katoh et al, 2005a,c;Emoto et al, 2008). There have also been some attempts to evaluate whether these mice can recapitulate the in vivo human metabolic profile of various xenobiotics (Foster et al, 2014). Some examples of these studies include CYP2D6-mediated metabolism of debrisoquine to 4-hydroxy debrisoquine (Katoh et al, 2007), CYP2C9-catalyzed conversion of S-warfarin to 7-hydroxywarfarin (Inoue et al, 2008(Inoue et al, , 2009, comparison with human metabolic profile of three different GSK drug candidates (De Serres et al, 2011), metabolism of ibuprofen and naproxen (Sanoh et al, 2012), and aldehyde oxidase-catalyzed oxidation of zaleplon (Tanoue et al, 2013).…”