In vivo drug discovery in the zebrafish

Abstract

The zebrafish has become a widely used model organism because of its fecundity, its morphological and physiological similarity to mammals, the existence of many genomic tools and the ease with which large phenotype-based screens can be performed. These attributes might also enable efficiency increases in several steps in the drug development process. Large-scale genetic and morpholino oligonucleotide screens allow unbiased discovery of genes that cause a desired phenotype. Zebrafish screens for genetic or epigenetic perturbations that suppress a disease phenotype can be used to discover novel therapeutic targets. Historically, numerous drugs have been discovered by observing phenotypic changes in whole animals exposed to small molecules, but these discoveries have often been serendipitous. Large-scale, systematic screens can be performed in the zebrafish to identify small molecules that can suppress disease phenotypes. At present, assessment of toxicity often occurs independently from efforts to discover lead compounds and improve their potency. High-throughput zebrafish toxicity assays combine many of the advantages of in vitro and in vivo toxicity models, making it possible to assess toxicity much earlier in the drug development process.