Article: RNAi and siRNA in target validation

Discussion in 'Health and medical' started by Robert Karl Sto, Apr 28, 2004.

  1. 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

    Posted by Robert Karl Stonjek.
     
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