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Nucleic Acids Research, 2003, Vol. 31, No. 21 6365-6372
© 2003 Oxford University Press

Expanding the design horizon of antisense oligonucleotides with alpha-L-LNA

Miriam Frieden, Signe M. Christensen, Nikolaj D. Mikkelsen, Christoph Rosenbohm, Charlotte A. Thrue, Majken Westergaard, Henrik F. Hansen, Henrik Ørum and Troels Koch*

Santaris Pharma A/S, Bøge Allé 3, DK-2970 Hørsholm, Denmark

*To whom correspondence should be addressed. Tel: +45 45179800; Fax: +45 45179898; Email: tk{at}santaris.com

Oligonucleotides containing Locked Nucleic Acids (LNA) to various extents and at various positions were evaluated for antisense activity, RNase H recruitment, nuclease stability and thermal affinity. In this work, two different diastereoisomers of LNA were studied: the beta-D-LNA and the alpha-L-LNA (abbreviated as ß-D-LNA and {alpha}-L-LNA). Our findings show that the best antisense activity with 16mer gapmers containing ß-D-LNA (oligonucleotides containing consecutive segments of LNA and DNA with a central DNA stretch flanked by two LNA segments, LNA–DNA–LNA) is found with gap sizes between 7 and 10 nt. The optimal gap size is motif-dependent, and requires the right balance between gap size and affinity. Compared to ß-D-LNA, {alpha}-L-LNA shows superior stability against a 3'-exonuclease. The design possibilities of {alpha}-L-LNA were explored for different gapmers and other designs, collectively called chimeras. The placement of {alpha}-L-LNA in the junctions or in the flanks resulted in potent antisense oligonucleotides. Moreover, different chimeras with an alternate composition of DNA, {alpha}-L-LNA and ß-D-LNA were evaluated in terms of antisense activity and RNase H recruitment. Chimeras with an interrupted DNA stretch with {alpha}-L-LNA still recruit RNase H and show good levels of antisense activity, while the same design with ß-D-LNA results in a drop in antisense potency. Our findings indicate that {alpha}-L-LNA is a powerful and versatile nucleotide analogue for designing potent antisense oligonucleotides.


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