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Proc Natl Acad Sci U S A. 2000 May 9;97(10):5633-8.

Potent and nontoxic antisense oligonucleotides containing locked nucleic acids.

Author information

1
Center for Genomics Research and Department of Neuroscience, Karolinska Institutet, S-171 77 Stockholm, Sweden. claes.wahlestedt@cgr.ki.se

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.

PMID:
10805816
PMCID:
PMC25880
[Indexed for MEDLINE]
Free PMC Article

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