Target Discovery and Validation Reviews and Protocols

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Main Approaches to Target Discovery and Validation
Mouldy Sioud
Summary
The identification and validation of disease-causing target genes is an essential first step in drug
discovery and development. Genomics and proteomics technologies have already begun to uncover
novel functional pathways and therapeutic targets in several human diseases such as cancers and
autoimmunity. Also, bioinformatics approaches have highlighted several key targets and functional
networks. In contrast to gene-profiling approaches, phenotype-oriented target identification allows
direct link between the genetic alterations and a disease phenotype. Therefore, identified genes are
more likely to be a cause rather than a consequence of the disease. Once a gene target or a mechanistic
pathway is identified, the next step is to demonstrate that it does play a critical role in disease
initiation, perpetuation, or both. A range of strategies exists for modulating gene expression in vitro
and in vivo. These strategies include the use of antibodies, negative dominant controls, antisense
oligonucleotides, ribozymes, and small-interfering RNAs. In contrast to in vitro assays, mouse
reverse genetics such as knockout phenotypes has become a powerful approach for deciphering
gene function and target validation in the context of mammalian physiology. In addition to diseasecausing
genes, the identification of antigens that stimulate both arms of the immune system is the
major goal for effective vaccine development. The hope is that target discovery and validation
processes will concurrently identify and validate therapeutic targets for drug intervention in
human diseases.
Key Words: Bioinformatics; genomics; microarray; protemics; target discovery; target validation;
transgenic animals; tumor antigens.
1. Introduction
1.1. Target Discovery
1.1.1. Genomics and Related Technologies
During the last decade, we have witnessed an enormous expansion in our
knowledge in understanding the molecular and cellular mechanisms underlying
From: Methods in Molecular Biology, vol. 360, Target Discovery and Validation Reviews and Protocols
Volume I, Emerging Strategies for Targets and Biomarker Discovery
Edited by: M. Sioud © Humana Press Inc., Totowa, NJ
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