A whole picture

345 technology and RNA interference (RNAi). In the realm of drug discovery, antisense technology — the use of short oligonucleotides to target specific messenger RNAs for destruction — was developed as a way of finding oligonucleotide-based drugs that interfere with gene expression, rather than with protein function. But the technology is currently enjoying greater success as a highthroughput method of target validation because it offers a highly specific and efficient way to inhibit the expression of potential target proteins in vitro and in vivo. GeneTrove, the genomics division of Isis Pharmaceuticals in Carlsbad, California, is one of the companies active in this field. It is focusing on the untapped pool of potential therapeutic target RNAs for both target validation and drug discovery, says Nicholas Dean, GeneTrove’s vice-president of functional genomics. It offers custom targetvalidation packages that include optimized antisense inhibitors against any target of interest and control oligonucleotides for testing in cell-culture model systems. It also applies antisense technology to target validation in vivo in animal models. Biognostik, a biotechnology company in Göttingen, Germany, offers a drugtarget validation kit that can be used in vitro or in vivo. It includes five targetspecific phosphorothioate antisense inhibitors and two random-sequence oligonucleotides to control for nonspecific effects. It has also developed a sequencedesign system called RADAR, which determines antisense oligonucleotides based on specificity, minimal nonspecific effects or protein binding, and the ability to be taken up into cells. Sequitur, a functional-genomics company in Natick, Massachusetts, has a slightly different approach to rapid target validation. It combines an antisense library with high-throughput DNA microarray assays to test the effects of the antisense molecules on gene expression. The company’s technology was used recently to validate a major therapeutic target for Alzheimer’s disease. Sequitur also carries out target validation based on RNAi (see ‘The silent treatment’, page 343). Custom phosphorothioate antisense oligonucleotides for research are available from firms such as Sigma-Genosys at the Woodlands, Texas; atugen in Berlin, Germany; and Integrated DNA Technologies in Coralville, Iowa. Gene Tools in Philomath, Oregon, offers morpholino antisense oligonucleotides, and Danish companies Cureon in Copenhagen and Exiqon in Vedbæk offer modified oligonucleotides based on ‘locked nucleic acid’ technology that can be used for antisense.