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Nucleic Acids Research, 2003, Vol. 31, No. 12 3185-3193
© 2003 Oxford University Press

Comparison of different antisense strategies in mammalian cells using locked nucleic acids, 2'-O-methyl RNA, phosphorothioates and small interfering RNA

Arnold Grünweller1, Eliza Wyszko1,2, Birgit Bieber1, Ricarda Jahnel1, Volker A. Erdmann1 and Jens Kurreck1

1 Freie Universität Berlin, Institut für Chemie–Biochemie, Thielallee 63, D-14195 Berlin, Germany and 2 Institute of Bioorganic Chemistry of the Polish Academy of Sciences, Noskowsiego 12, 61794 Poznan, Poland

*To whom correspondence should be addressed. Tel: +49 30 83 85 69 69; Fax: +49 30 83 85 64 13; Email: jkurreck{at}chemie.fu-berlin.de

Locked nucleic acids (LNAs) and double-stranded small interfering RNAs (siRNAs) are rather new promising antisense molecules for cell culture and in vivo applications. Here, we compare LNA–DNA–LNA gapmer oligonucleotides and siRNAs with a phosphorothioate and a chimeric 2'-O-methyl RNA–DNA gapmer with respect to their capacities to knock down the expression of the vanilloid receptor subtype 1 (VR1). LNA–DNA–LNA gapmers with four or five LNAs on either side and a central stretch of 10 or 8 DNA monomers in the center were found to be active gapmers that inhibit gene expression. A comparative co-transfection study showed that siRNA is the most potent inhibitor of VR1–green fluorescent protein (GFP) expression. A specific inhibition was observed with an estimated IC50 of 0.06 nM. An LNA gapmer was found to be the most efficient single-stranded antisense oligonucleotide, with an IC50 of 0.4 nM being 175-fold lower than that of commonly used phosphorothioates (IC50 ~70 nM). In contrast, the efficiency of a 2'-O-methyl-modified oligonucleotide (IC50 ~220 nM) was 3-fold lower compared with the phosphorothioate. The high potency of siRNAs and chimeric LNA–DNA oligonucleotides make them valuable candidates for cell culture and in vivo applications targeting the VR1 mRNA.


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