Genetically engineered animals in drug discovery and development: a maturing resource for toxicologic research

Area of Science:

• Toxicology
• Genetics
• Pharmacology
• Biotechnology

Background:

• Genetically engineered mice (GEMs), including transgenic, knock-out, and knock-in models, are crucial tools in biomedical research.
• Advancements in GEM technology enable more sophisticated disease modeling and therapeutic target evaluation.
• Traditional toxicity testing methods face limitations in speed and relevance.

Purpose of the Study:

• To review the expanding role and applications of GEMs in toxicological research.
• To highlight recent innovations in GEM development relevant to toxicity assessment.
• To discuss the interpretation of toxicity data derived from GEMs and their future potential.

Main Methods:

• Utilizing GEMs with multiple engineered genes, inducible mutations, and humanized gene substitutions for in vivo studies.
• Applying GEMs for basic mechanistic research and applied screening of genotoxicity and carcinogenicity.
• Comparing toxicity data from GEMs with traditional bioassays.

Main Results:

• GEMs facilitate in vivo investigation of xenobiotic toxicity, particularly 'humanized' mice.
• GEMs are used in both fundamental research and practical screening for genotoxicity and carcinogenicity.
• GEMs often exhibit a higher incidence of lesions with shorter latency compared to wild-type controls.

Conclusions:

• GEMs are becoming indispensable for understanding disease mechanisms and evaluating drug candidates.
• Careful characterization of GEM phenotypes and consideration of compensatory mechanisms are essential for data interpretation.
• Toxicity data from GEMs are supplementing, and likely will eventually replace, traditional bioassay results.