Short locked nucleic acid antisense oligonucleotides potently reduce apolipoprotein B mRNA and serum cholesterol in mice and non-human primates
| Autor: | Niels Fisker, Ellen Marie Straarup, Henrik Ørum, Henrik Frydenlund Hansen, Christoph Rosenbohm, Jens Bo Hansen, Vibeke Aarup, Troels Koch, Marie Lindholm, Maj Hedtjärn |
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| Rok vydání: | 2010 |
| Předmět: |
Apolipoprotein B
Base Pair Mismatch Oligonucleotides Mice chemistry.chemical_compound In vivo Cell Line Tumor Genetics Animals Humans Potency RNA Messenger Locked nucleic acid Molecular Biology Apolipoproteins B biology Oligonucleotide Cholesterol Oligonucleotides Antisense Molecular biology In vitro Mice Inbred C57BL Macaca fascicularis Biochemistry chemistry Nucleic acid biology.protein Autoradiography Female |
| Zdroj: | Nucleic Acids Research |
| ISSN: | 1362-4962 0305-1048 |
| DOI: | 10.1093/nar/gkq457 |
| Popis: | The potency and specificity of locked nucleic acid (LNA) antisense oligonucleotides was investigated as a function of length and affinity. The oligonucleotides were designed to target apolipoprotein B (apoB) and were investigated both in vitro and in vivo. The high affinity of LNA enabled the design of short antisense oligonucleotides (12- to 13-mers) that possessed high affinity and increased potency both in vitro and in vivo compared to longer oligonucleotides. The short LNA oligonucleotides were more target specific, and they exhibited the same biodistribution and tissue half-life as longer oligonucleotides. Pharmacology studies in both mice and non-human primates were conducted with a 13-mer LNA oligonucleotide against apoB, and the data showed that repeated dosing of the 13-mer at 1-2 mg/kg/week was sufficient to provide a significant and long lasting lowering of non-high-density lipoprotein (non-HDL) cholesterol without increasing serum liver toxicity markers. The data presented here show that oligonucleotide length as a parameter needs to be considered in the design of antisense oligonucleotide and that potent short oligonucleotides with sufficient target affinity can be generated using the LNA chemistry. Conclusively, we present a 13-mer LNA oligonucleotide with therapeutic potential that produce beneficial cholesterol lowering effect in non-human primates. |
| Databáze: | OpenAIRE |
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