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Nucleic Acids Research 2006 34(6):1669-1675; doi:10.1093/nar/gkl033
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Published online 22 March 2006

© The Author 2006. Published by Oxford University Press. 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, please contact journals.permissions@oxfordjournals.org

Article

Improvements in siRNA properties mediated by 2'-deoxy-2'-fluoro-ß-D-arabinonucleic acid (FANA)

Thomas Dowler, Denis Bergeron, Anna-Lisa Tedeschi, Luc Paquet, Nicolay Ferrari and Masad J. Damha1,*

Topigen Pharmaceuticals Inc. 2901 East Rachel Street, Room 13, Montreal, Quebec, Canada H1W 4A4 1Department of Chemistry, Otto Maass Chemistry Building, McGill University 801 Sherbrooke Street West, Montreal, Quebec, Canada H3A 2K6

*To whom correspondence should be addressed. Tel: +1 514 398 7552; Fax: +1 514 398 3797; Email: masad.damha{at}mcgill.ca

Received December 16, 2005. Revised January 4, 2006. Accepted February 20, 2006.

RNA interference (RNAi) has emerged recently as an efficient mechanism for specific gene silencing. Short double-stranded small interfering RNAs (siRNAs) are now widely used for cellular or drug target validation; however, their use for silencing clinically relevant genes in a therapeutic setting remains problematic because of their unfavourable metabolic stability and pharmacokinetic properties. To address some of these concerns, we have investigated the properties of siRNA modified with 2'-deoxy-2'-fluoro-ß-D-arabinonucleotide units (araF-N or FANA units). Here we provide evidence that these modified siRNAs are compatible with the intracellular RNAi machinery and can mediate specific degradation of target mRNA. We also show that the incorporation of FANA units into siRNA duplexes increases activity and substantially enhances serum stability of the siRNA. A fully modified sense 2'-deoxy-2'-fluoro-ß-D-arabinonucleic acid (FANA) strand when hybridized to an antisense RNA (i.e. FANA/RNA hybrid) was shown to be 4-fold more potent and had longer half-life in serum (~6 h) compared with an unmodified siRNA (<15 min). While incorporation of FANA units is well tolerated throughout the sense strand of the duplex, modifications can also be included at the 5' or 3' ends of the antisense strand, in striking contrast to other commonly used chemical modifications. Taken together, these results offer preliminary evidence of the therapeutic potential of FANA modified siRNAs.

Correspondence may also be addressed to Nicolay Ferrari. Tel: +1 514 868 0077; Fax: +1 514 868 0011; Email: nicolay.ferrari{at}topigen.com


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