Generation and Use of Transgenic Mice in Drug Discovery

Abstract

IntroductionOne of the major challenges for the pharmaceutical industry is to develop drugs for new targets in order to fulfill the yet unmet medical needs, especially in fields such as neuropharmacology and complex polygenic disorders. Defining gene function and target validation are key steps for selecting a gene sequence for drug development. With rapid advances and scale-up of DNA sequencing, 20 000 protein-coding genes and even more noncoding genes have been identified in humans. The question is how to assign functions to each of these genes in the context of a whole organism, in normal physiology and development, as well as the contribution of mutant alleles to inherited diseases or challenged environmental conditions.With all the various technologies now available to manipulate the genome, the comparison of a functional and a nonfunctional (mutant) state will provide insight into the in vivo function of a given gene. However, understanding the pathogenicity of a given allelic variant found in the human population is still a challenge. Unlocking the functional role of the mammalian genome will have a transformative effect on biology and biotechnological innovations and also on the understanding of human diseases. It will allow the scientific community to identify and validate new candidate targets for drug development. Importantly, such approaches will also allow the assessment of the risk associated with specific target invalidation, a mandatory and key step in drug development and translational medicine.Therefore, analysis of the function of genes, also called functional genomics or phenogenomics, constitutes a bottleneck that slows down the whole process of target and drug discovery. With its genome amenable to manipulation and its physiology and genome sequence homology close to human (99% of mouse genes have human homologs) the mouse has become the animal model of choice for deciphering gene function, identifying putative targets and pathways involved in pathogenesis and modeling human genetic diseases, and will probably stay the leading model to test new therapeutic molecules. The use of the mouse as a model 131In Vivo Models for Drug Discovery, First Edition. Edited