Applications and considerations for the use of genetically engineered mouse models in drug development

Considering high drug attrition rates in clinical studies and the overall complexity and challenging environment of drug development, it is increasingly important to understand the therapeutic molecule and target and how they intersect with disease biology as fully as possible. This requires one to use numerous tools and investigative approaches in combination. Genetically engineered mouse models are a critical component to the drug development toolbox as they can provide key insights across multiple steps of the drug development process. While knock-out and knock-in mice can inform questions of basic biology, genetically engineered mice can also be applied to model diseases for efficacy studies, to discriminate on-target and off-target effects of novel therapeutics, and to inform an array of biologic and pharmacologic questions, including pharmacodynamics, pharmacokinetics, and biomarker discovery. However, use of these models requires not only an understanding of their strengths and limitations but also a careful consideration of the context in which they are being used and the hypotheses being addressed by them. Additionally, they should not be used in isolation, but instead in combination with other biochemical, in vitro, and clinical data to create a broad understanding of the drug, target, and disease biology.