Chapter 27. Transgenic and Gene Targeting Technology in Drug Discovery

Abstract

The fast and efficient development of new pharmaceuticals requires the availability of high throughput biological test systems to identify and characterize potentially therapeutic agents prior to human clinical trials. Historically, lead compounds have often been identified by random screening of chemical or fermentation product libraries. Peptide, oligonucleotide, carbohydrate, and combinatorial chemical libraries have now been added to the list of novel structure sources from that to identify new chemical leads. Ideally, for rapid and economical development of new pharmaceuticals the biological test systems, used to identify and characterize new lead compounds, should mimic as closely as possible the human condition being targeted. The use of transgenic animals could prove to be a remarkable technical advance for drug development. These transgenic models could provide distinct advantages in identifying disease treatments that have eluded the more classical screening approaches. This approach could also allow the pharmaceutical and biotechnology industries to move lead compounds from animals to human clinical trials more efficiently and cost effectively. Validated transgenic animal models, containing the genetic material that simulate human pathophysiological disease states, are more relevant models for evaluating lead compounds obtained from high output bioassay screens. Ameliorating symptoms or altering biochemical events in such models could reduce the need for more exhaustive, costly, and time consuming tests, associated with the more classical screening approaches. Moreover, efficacy testing of lead compounds in transgenic models could significantly reduce the number of animals on study, and yet be more predicative of success in the clinic.