Use of Genetically Modified Animal Models in Discovery Toxicology

3 USE OF GENETICALLY MODIFIED ANIMAL MODELS IN DISCOVERY TOXICOLOGY 

One can also speculate that heterozygous KO mice might be more relevant and representative of partial pharmacological target modulation (i.e., 50% target inhibition), but even when these mice can be useful for interrogating dose-response relationships, they can also underestimate safety issues, especially in situations where robust target modulation (i.e., 50%) is needed for efficacy. 

If a molecule targets two different isoforms of a protein, either by design or by the inability to obtain selectivity among closely related isoforms, the most relevant KOs for safety evaluation should be dual KOs of the targeted isoforms. An example that illustrates the complexities of drug target KOs and that incorporates embryo lethal phenotypes, tissue-specific KO, and dual isoform KOs is provided by MEK KOs. 

One MEK inhibitor, Trametinib, has been approved, and several others are in clinical trials for oncology indications (Akinleye et al., 2013) these inhibitors target both MEKl and MEK2 isoforms. MEK2 KO mice are phenotypicaUy normal (Belanger et al., 2003), whereas MEKl KO mice die 

This example emphasizes the importance of not discounting phenotypic findings, even if these findings are not recapitulated in rodent toxicology studies as the findings may still remain relevant in other species or with inCTeased target engagement. 

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