Target Validation Mouse Models

Conventional knockout provides complete target elimination from conception, revealing maximum biological effect but may cause embryonic lethality or developmental compensation. Conditional knockout enables tissue specific or temporal target validation, modeling pharmacological intervention in adult animals, which is more translatable for drug development.

Use inducible knockout when modeling drug target inhibition (requires adult-onset deletion), when avoiding developmental compensation is important, or when studying acute vs chronic phenotypes. Inducible systems most closely model therapeutic target inhibition because patients have normal target function before treatment, and drug administration causes acute target inhibition.

Humanized models express human target genes, enabling preclinical testing of therapeutics that target human-specific proteins. This is essential for monoclonal antibodies with species-specific epitopes, checkpoint inhibitors requiring human immune molecules, and other therapeutics that don't cross-react with mouse targets.

Essential controls include wild-type littermates (genetic background control), Cre-positive flox-negative controls (to detect Cre toxicity), vehicle-treated controls (for inducible systems), and heterozygous carriers (dose-response curve). Multiple controls ensure phenotypes are due to target deletion, not experimental artifacts.