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Nucleic Acids Research 2005 33(1):439-447; doi:10.1093/nar/gki193
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Published online 14 January 2005

© 2005, the authors Nucleic Acids Research, Vol. 33 No. 1 © Oxford University Press 2005; all rights reserved
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use permissions, please contact journals.permissions{at}oupjournals.org.

Article

Locked nucleic acid (LNA) mediated improvements in siRNA stability and functionality

Joacim Elmén*, Håkan Thonberg, Karl Ljungberg1, Miriam Frieden2, Majken Westergaard2, Yunhe Xu, Britta Wahren1, Zicai Liang, Henrik Ørum2, Troels Koch2 and Claes Wahlestedt

Center for Genomics and Bioinformatics, Karolinska Institutet 171 77 Stockholm, Sweden 1 Department of Virology, Swedish Institute for Infectious Disease Control 171 82 Solna, Sweden 2 Santaris Pharma A/S Bøge allé 3, DK-2970 Hørsholm, Denmark

*To whom correspondence should be addressed. Tel: +46 8 524 86697; Fax: +46 8 32 39 50; Email: joacim.elmen{at}cgb.ki.se

Received October 6, 2004. Revised December 23, 2004. Accepted December 23, 2004.

Therapeutic application of the recently discovered small interfering RNA (siRNA) gene silencing phenomenon will be dependent on improvements in molecule bio-stability, specificity and delivery. To address these issues, we have systematically modified siRNA with the synthetic RNA-like high affinity nucleotide analogue, Locked Nucleic Acid (LNA). Here, we show that incorporation of LNA substantially enhances serum half-life of siRNA's, which is a key requirement for therapeutic use. Moreover, we provide evidence that LNA is compatible with the intracellular siRNA machinery and can be used to reduce undesired, sequence-related off-target effects. LNA-modified siRNAs targeting the emerging disease SARS, show improved efficiency over unmodified siRNA on certain RNA motifs. The results from this study emphasize LNA's promise in converting siRNA from a functional genomics technology to a therapeutic platform.


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