主催: 日本毒性学会
会議名: 第47回日本毒性学会学術年会
開催日: 2020 -
In the early discovery stage, oftentimes, the biology of novel drug targets is largely unknown, and toxicologists may need to support project teams with limited information about target safety. Historically, there has been a strong concordance between the phenotypes of genetically engineered rodent models (GERMs) and pharmacology of the human target, which has emphasized the applicability of GERMs in the understanding of potential on-target toxicities to humans. However, germline ablation often proves to be embryonic lethal for many targets and, consequently, only limited information from tissue-specific gene modifications is available. Moreover, therapeutic agents may result in systemic effects not well-predicted by these animal models. Herein, we discuss the value of temporally controlled conditional knockout (cKO) or knockdown (cKD) rodents, where the expression of the gene of interest is systemically deleted or reduced, respectively, from a given time by use of an inducer. In our experience, systemic cKO or cKD animals have been useful for unveiling potential safety liabilities to the intended patient population and, hence, customizing safety strategy for specific targets. Additionally, they can be utilized to investigate mechanisms of toxicity of compounds in development. In this presentation, we focus on how we have leveraged GERMs in safety de-risking and decision-making in the discovery stage as well as potential challenges and pitfalls associated with GERMs that toxicologists should be take into consideration.