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 [1] 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

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