日本毒性学会学術年会
第47回日本毒性学会学術年会
セッションID: W8-1
会議情報

ワークショップ8
Utility of genetically engineered rodent models during drug discovery: case studies to support target safety assessment and mechanistic investigation
*Satoko KAKIUCHI-KIYOTA
著者情報
会議録・要旨集 フリー

詳細
抄録

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.

著者関連情報
© 2020 日本毒性学会
前の記事 次の記事
feedback
Top