R
Robert Karl Sto
Guest
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.
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.