Genetically Engineered Mouse Models for Drug Discovery: New Chemical Genetic Approaches

摘要

While standard transgenic and knockout mouse technologies have provided anwealth of information for target selection and validation, there have been great advances innusing more sophisticated modeling techniques to achieve temporal and spatial regulation ofnindividual genes in adult animals. Recent developments in RNA interference (RNAi)ntechnology in in vivo models promise to further improve upon the static and irreversiblenfeatures of gene knockouts. Chemical genetic approaches create novel functional alleles ofntargets and allow fine modulation of protein function in vivo by small molecules, providingnthe most pharmacologically relevant target validation. Using these advanced models, onencan not only ask whether the function of the target is critical for the initiation and maintenance of the disease, but alsonwhether therapies designed to alter the function of the target would be safe and efficacious. In this review, we describenvarious in vivo tools for target validation in mouse models, discuss advantages and disadvantages of each approach, andngive examples of their impact on drug discovery.