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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.
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“In the CNS, where enzymatic degradation is a concern, stabilizing modifications help prolong the half-life of therapeutic microRNAs.197,198,199”
From MiR-128-3p – a gray eminence of the human central nervous system (2024) · cites this paper as [197]
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Zhou, W., & Agrawal, S. (1998) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/s0960-894x(98)00591-5 · Cited by 41
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Sorted by citations
LNA (Locked Nucleic Acid): High-Affinity Targeting of Complementary RNA and DNA
Vester, B., & Wengel, J. (2004) · Biochemistry · doi:10.1021/bi0485732 · Cited by 727
Self-citationMicroRNA-Based Diagnosis and Therapy
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Metadata
- Authors
- 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.
- Affiliations
- Center for Genomics Research and Department of Neuroscience, Karolinska Institutet, S-171 77 Stockholm, Sweden; Department of Pharmacology, University of Arizona, Tucson, AZ 85724; Exiqon A/S, Copenhagen, DK-2950 Vedbaek, Denmark; Department of Tumor Endocrinology, Institute of Cancer Biology, Danish Cancer Society, DK-2100 Copenhagen, Denmark; and Department of Chemistry, University of Copenhagen, DK-2100 Copenhagen, Denmark
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2000-05-09
- Volume
- 97
- Issue
- 10
- Pages
- 5633-5638
- ISSN
- 0027-8424
- 1091-6490
- Cited by
- 520
- References
- 2
- Language
- en
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