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Potent and nontoxic antisense oligonucleotides containing locked nucleic acids.


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.

SUBMITTER: Wahlestedt C 

PROVIDER: S-EPMC25880 | biostudies-literature | 2000 May

REPOSITORIES: biostudies-literature

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Potent and nontoxic antisense oligonucleotides containing locked nucleic acids.

Wahlestedt C C   Salmi P P   Good L L   Kela J J   Johnsson T T   Hökfelt T T   Broberger C C   Porreca F F   Lai J J   Ren K K   Ossipov M M   Koshkin A A   Jakobsen N N   Skouv J J   Oerum H H   Jacobsen M H MH   Wengel J J  

Proceedings of the National Academy of Sciences of the United States of America 20000501 10


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 oligo  ...[more]

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