1. Potent and nontoxic antisense oligonucleotides containing locked nucleic acids
- Author
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Liam Good, Tomas Hökfelt, Henrik Oerum, Alexei A. Koshkin, Frank Porreca, Jesper Wengel, Kunkun Ren, Thomas Johnsson, Michael H. Ossipov, Nana Jakobsen, Josephine Lai, Claes Wahlestedt, Johanna Kela, Christian Broberger, Mogens Havsteen Jacobsen, Peter Salmi, and Jan Skouv
- Subjects
Ribonuclease H ,Breast Neoplasms ,Cerebral Ventricles ,Oligodeoxyribonucleotides, Antisense ,Stereotaxic Techniques ,chemistry.chemical_compound ,Blood serum ,Receptors, Opioid, delta ,Tumor Cells, Cultured ,Animals ,Humans ,Locked nucleic acid ,RNase H ,Reporter gene ,Multidisciplinary ,Base Sequence ,biology ,Oligonucleotide ,Putamen ,Biological Transport ,Biological Sciences ,Thionucleotides ,Molecular biology ,Rats ,Enzyme Activation ,chemistry ,Biochemistry ,Drug Design ,Stereotaxic technique ,biology.protein ,Nucleic acid ,Female ,Caudate Nucleus ,DNA - 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.
- Published
- 2000
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