Defining Therapeutic Targets in Simple Model Organisms

The progress in genome-scale approaches to human diseases will soon require to understand the function of a large number of genes as potentially interesting therapeutic targets. The determination of their biological role needs to be accelerated in order to select valid therapeutic targets and streamline the drug discovery process. The sequencing of the human genome, as well as a number of model organisms, provides a strong framework to achieve this goal. Several methods among which gene expression profiling and protein interaction mapping are being used on a large-scale basis and constitute useful entry points to identify pathways involved in disease mechanisms. The resulting information is however limited. Other methods rely on the genetic manipulation of well-characterized and simple model organisms (SMOs) to reconstruct human disease-associated pathways and pinpoint biologically-valid therapeutic targets on the basis of function-based datasets generated in vivo. SMOs are strongly complementary to well-established complex mammalian models, and multiple ways exist to integrate SMOs into the early stage of the drug discovery process. In this review, we attempt to highlight some of the general criteria and essential methodological components associated with the use of SMO technologies for rapid functional genomics. Examples are provided to illustrate the utility of C. elegans and Drososphila for the validation of targets for central nervous system drugs.