RNAi and siRNA in target validation Kewal K. Jain Drug Discovery Today 2004, 9:307-309 Gene silencing by RNA interference (RNAi) technologies has made considerable progress in the last few years  and small interfering RNAs (siRNAs) have become a preferred modality for target validation, which was the theme of the 4th International Conference on RNAi and siRNA, organized by IBC Life Sciences in Zurich, Switzerland from 3-4 February 2004. Genomic and proteomic technologies have helped to discover a plethora of drug targets, in turn creating a bottleneck in the drug discovery process that is being tackled with target validation using RNAi technologies. However, the problems of delivery and off-target effects, as well as poor tissue distribution, present significant challenges, as pointed out by Clive Jackson of AstraZeneca (http://www.astrazeneca.com) in his opening talk. Success criterion at AstraZeneca is 85% of message knockout and this was achieved for a kinase in the synovial fibroblast. The Global Target Validation Network within AstraZeneca is monitoring the success of siRNA across the company in different biological systems and disease areas. The design of siRNA experiments draws on general observations on gene silencing studies with RNase H antisense as well as experience with siRNA sequence selection and delivery optimization. Jackson pointed out that it is often necessary to confirm function by alternative approaches to siRNA in a full target validation package. Sumedha Jayasena of Amgen (http://www.amgen.com) reviewed the benefits and drawbacks of RNAi for target validation. Certain siRNAs can silence 'off-targets', induce an interferon response, silence chromatin and lead to false conclusions on end points. To maximize the benefits of using siRNA, Jayasena called for a better understanding of the mechanism of siRNA action, intelligent approaches to siRNA design and chemical modification, and better screening for non-specific effects. To avoid undesirable effects of siRNAs, one should identify highly potent siRNAs that can be effective at low nanomolar concentrations. Internal stability of siRNAs should be achieved during the design stage to reduce participation of the sense strand. Finally, chemical modification of siRNA can reduce or eliminate nonspecific and off-target effects. Read the rest at BioMedNet http://gateways.bmn.com/magazine- /article?pii=S1359644604030508 Posted by Robert Karl Stonjek.