Potent and nontoxic antisense oligonudeotides containing locked nucleic acids

Claes Wahlestedt, Peter Salmi, Liam Good, Johanna Kela, Thomas Johnsson, Tomas Hökfelt, Christian Broberger, Frank Porreca, Josephine Lai, Kunkun Ren, Michael Ossipov, Alexei Koshkin, Nana Jakobsen, Jan Skouv, Henrik Oerum, Mogens Havsteen Jacobsen, Jesper Wengel

Research output: Contribution to journalArticle

473 Scopus citations

Abstract

Insufficient efficacy and/or specificity of antisense oligonucleotides limit their in vivo usefulness. We demonstrate here that a high-affinity DNA analog, locked nucleic acid (LNA), confers several desired properties to antisense agents. Unlike DNA, LNA/DNA copolymers were not degraded readily in blood serum and cell extracts. However, like DNA, the LNA/DNA copolymers were capable of activating RNase H, an important antisense mechanism of action. In contrast to phosphorothioate-containing oligonucleotides, isosequential LNA analogs did not cause detectable toxic reactions in rat brain. LNA/DNA copolymers exhibited potent antisense activity on assay systems as disparate as a G-protein-coupled receptor in living rat brain and an Escherichia coli reporter gene. LNA-containing oligonucleotides will likely be useful for many antisense applications.

Original languageEnglish (US)
Pages (from-to)5633-5638
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume97
Issue number10
DOIs
StatePublished - May 9 2000
Externally publishedYes

ASJC Scopus subject areas

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    Wahlestedt, C., Salmi, P., Good, L., Kela, J., Johnsson, T., Hökfelt, T., Broberger, C., Porreca, F., Lai, J., Ren, K., Ossipov, M., Koshkin, A., Jakobsen, N., Skouv, J., Oerum, H., Jacobsen, M. H., & Wengel, J. (2000). Potent and nontoxic antisense oligonudeotides containing locked nucleic acids. Proceedings of the National Academy of Sciences of the United States of America, 97(10), 5633-5638. https://doi.org/10.1073/pnas.97.10.5633