Short locked nucleic acid antisense oligonucleotides potently reduce apolipoprotein B mRNA and serum cholesterol in mice and non-human primates
Identifieur interne : 001350 ( Pmc/Checkpoint ); précédent : 001349; suivant : 001351Short locked nucleic acid antisense oligonucleotides potently reduce apolipoprotein B mRNA and serum cholesterol in mice and non-human primates
Auteurs : Ellen Marie Straarup ; Niels Fisker ; Maj Hedtj Rn ; Marie W. Lindholm ; Christoph Rosenbohm ; Vibeke Aarup ; Henrik Frydenlund Hansen ; Henrik Rum ; Jens B. Rode Hansen ; Troels KochSource :
- Nucleic Acids Research [ 0305-1048 ] ; 2010.
Abstract
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
Url:
DOI: 10.1093/nar/gkq457
PubMed: 20615897
PubMed Central: 2978335
Affiliations:
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<author><name sortKey="Fisker, Niels" sort="Fisker, Niels" uniqKey="Fisker N" first="Niels" last="Fisker">Niels Fisker</name>
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<author><name sortKey="Lindholm, Marie W" sort="Lindholm, Marie W" uniqKey="Lindholm M" first="Marie W." last="Lindholm">Marie W. Lindholm</name>
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<author><name sortKey="Rosenbohm, Christoph" sort="Rosenbohm, Christoph" uniqKey="Rosenbohm C" first="Christoph" last="Rosenbohm">Christoph Rosenbohm</name>
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<author><name sortKey=" Rum, Henrik" sort=" Rum, Henrik" uniqKey=" Rum H" first="Henrik" last=" Rum">Henrik Rum</name>
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<author><name sortKey="Hansen, Jens B Rode" sort="Hansen, Jens B Rode" uniqKey="Hansen J" first="Jens B. Rode" last="Hansen">Jens B. Rode Hansen</name>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Short locked nucleic acid antisense oligonucleotides potently reduce apolipoprotein B mRNA and serum cholesterol in mice and non-human primates</title>
<author><name sortKey="Straarup, Ellen Marie" sort="Straarup, Ellen Marie" uniqKey="Straarup E" first="Ellen Marie" last="Straarup">Ellen Marie Straarup</name>
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<author><name sortKey="Fisker, Niels" sort="Fisker, Niels" uniqKey="Fisker N" first="Niels" last="Fisker">Niels Fisker</name>
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<author><name sortKey="Hedtj Rn, Maj" sort="Hedtj Rn, Maj" uniqKey="Hedtj Rn M" first="Maj" last="Hedtj Rn">Maj Hedtj Rn</name>
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<author><name sortKey="Lindholm, Marie W" sort="Lindholm, Marie W" uniqKey="Lindholm M" first="Marie W." last="Lindholm">Marie W. Lindholm</name>
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<author><name sortKey="Rosenbohm, Christoph" sort="Rosenbohm, Christoph" uniqKey="Rosenbohm C" first="Christoph" last="Rosenbohm">Christoph Rosenbohm</name>
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<author><name sortKey="Aarup, Vibeke" sort="Aarup, Vibeke" uniqKey="Aarup V" first="Vibeke" last="Aarup">Vibeke Aarup</name>
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<author><name sortKey="Hansen, Henrik Frydenlund" sort="Hansen, Henrik Frydenlund" uniqKey="Hansen H" first="Henrik Frydenlund" last="Hansen">Henrik Frydenlund Hansen</name>
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<author><name sortKey=" Rum, Henrik" sort=" Rum, Henrik" uniqKey=" Rum H" first="Henrik" last=" Rum">Henrik Rum</name>
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<author><name sortKey="Hansen, Jens B Rode" sort="Hansen, Jens B Rode" uniqKey="Hansen J" first="Jens B. Rode" last="Hansen">Jens B. Rode Hansen</name>
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<author><name sortKey="Koch, Troels" sort="Koch, Troels" uniqKey="Koch T" first="Troels" last="Koch">Troels Koch</name>
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<series><title level="j">Nucleic Acids Research</title>
<idno type="ISSN">0305-1048</idno>
<idno type="eISSN">1362-4962</idno>
<imprint><date when="2010">2010</date>
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<front><div type="abstract" xml:lang="en"><p>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 <italic>in vitro</italic>
and <italic>in vivo</italic>
. The high affinity of LNA enabled the design of short antisense oligonucleotides (12- to 13-mers) that possessed high affinity and increased potency both <italic>in vitro</italic>
and <italic>in vivo</italic>
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.</p>
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</TEI>
<pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Nucleic Acids Res</journal-id>
<journal-id journal-id-type="iso-abbrev">Nucleic Acids Res</journal-id>
<journal-id journal-id-type="publisher-id">nar</journal-id>
<journal-id journal-id-type="hwp">nar</journal-id>
<journal-title-group><journal-title>Nucleic Acids Research</journal-title>
</journal-title-group>
<issn pub-type="ppub">0305-1048</issn>
<issn pub-type="epub">1362-4962</issn>
<publisher><publisher-name>Oxford University Press</publisher-name>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">20615897</article-id>
<article-id pub-id-type="pmc">2978335</article-id>
<article-id pub-id-type="doi">10.1093/nar/gkq457</article-id>
<article-id pub-id-type="publisher-id">gkq457</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Molecular Biology</subject>
</subj-group>
</article-categories>
<title-group><article-title>Short locked nucleic acid antisense oligonucleotides potently reduce apolipoprotein B mRNA and serum cholesterol in mice and non-human primates</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Straarup</surname>
<given-names>Ellen Marie</given-names>
</name>
</contrib>
<contrib contrib-type="author"><name><surname>Fisker</surname>
<given-names>Niels</given-names>
</name>
</contrib>
<contrib contrib-type="author"><name><surname>Hedtjärn</surname>
<given-names>Maj</given-names>
</name>
</contrib>
<contrib contrib-type="author"><name><surname>Lindholm</surname>
<given-names>Marie W.</given-names>
</name>
</contrib>
<contrib contrib-type="author"><name><surname>Rosenbohm</surname>
<given-names>Christoph</given-names>
</name>
</contrib>
<contrib contrib-type="author"><name><surname>Aarup</surname>
<given-names>Vibeke</given-names>
</name>
</contrib>
<contrib contrib-type="author"><name><surname>Hansen</surname>
<given-names>Henrik Frydenlund</given-names>
</name>
</contrib>
<contrib contrib-type="author"><name><surname>Ørum</surname>
<given-names>Henrik</given-names>
</name>
</contrib>
<contrib contrib-type="author"><name><surname>Hansen</surname>
<given-names>Jens B. Rode</given-names>
</name>
</contrib>
<contrib contrib-type="author"><name><surname>Koch</surname>
<given-names>Troels</given-names>
</name>
<xref ref-type="corresp" rid="COR1">*</xref>
</contrib>
</contrib-group>
<aff>Santaris Pharma A/S, Kogle Allé 6, DK-2970 Hørsholm, Denmark</aff>
<author-notes><corresp id="COR1">*To whom correspondence should be addressed. Tel: <phone>+45 45 17 98 08</phone>
; Fax: <fax>+45 45 17 98 10</fax>
; Email: <email>tk@santaris.com</email>
</corresp>
<fn><p>The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.</p>
</fn>
</author-notes>
<pub-date pub-type="ppub"><month>11</month>
<year>2010</year>
</pub-date>
<pub-date pub-type="epub"><day>8</day>
<month>7</month>
<year>2010</year>
</pub-date>
<pub-date pub-type="pmc-release"><day>08</day>
<month>7</month>
<year>2010</year>
</pub-date>
<pmc-comment> PMC Release delay is 0 months and 0 days and was based on the
. </pmc-comment>
<volume>38</volume>
<issue>20</issue>
<fpage>7100</fpage>
<lpage>7111</lpage>
<history><date date-type="received"><day>7</day>
<month>4</month>
<year>2010</year>
</date>
<date date-type="rev-recd"><day>10</day>
<month>5</month>
<year>2010</year>
</date>
<date date-type="accepted"><day>10</day>
<month>5</month>
<year>2010</year>
</date>
</history>
<permissions><copyright-statement>© The Author(s) 2010. Published by Oxford University Press.</copyright-statement>
<copyright-year>2010</copyright-year>
<license license-type="creative-commons" xlink:href="http://creativecommons.org/licenses/by-nc/2.5"><license-p><pmc-comment>CREATIVE COMMONS</pmc-comment>
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by-nc/2.5">http://creativecommons.org/licenses/by-nc/2.5</ext-link>
), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.</license-p>
</license>
</permissions>
<abstract><p>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 <italic>in vitro</italic>
and <italic>in vivo</italic>
. The high affinity of LNA enabled the design of short antisense oligonucleotides (12- to 13-mers) that possessed high affinity and increased potency both <italic>in vitro</italic>
and <italic>in vivo</italic>
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.</p>
</abstract>
</article-meta>
</front>
</pmc>
<affiliations><list></list>
<tree><noCountry><name sortKey=" Rum, Henrik" sort=" Rum, Henrik" uniqKey=" Rum H" first="Henrik" last=" Rum">Henrik Rum</name>
<name sortKey="Aarup, Vibeke" sort="Aarup, Vibeke" uniqKey="Aarup V" first="Vibeke" last="Aarup">Vibeke Aarup</name>
<name sortKey="Fisker, Niels" sort="Fisker, Niels" uniqKey="Fisker N" first="Niels" last="Fisker">Niels Fisker</name>
<name sortKey="Hansen, Henrik Frydenlund" sort="Hansen, Henrik Frydenlund" uniqKey="Hansen H" first="Henrik Frydenlund" last="Hansen">Henrik Frydenlund Hansen</name>
<name sortKey="Hansen, Jens B Rode" sort="Hansen, Jens B Rode" uniqKey="Hansen J" first="Jens B. Rode" last="Hansen">Jens B. Rode Hansen</name>
<name sortKey="Hedtj Rn, Maj" sort="Hedtj Rn, Maj" uniqKey="Hedtj Rn M" first="Maj" last="Hedtj Rn">Maj Hedtj Rn</name>
<name sortKey="Koch, Troels" sort="Koch, Troels" uniqKey="Koch T" first="Troels" last="Koch">Troels Koch</name>
<name sortKey="Lindholm, Marie W" sort="Lindholm, Marie W" uniqKey="Lindholm M" first="Marie W." last="Lindholm">Marie W. Lindholm</name>
<name sortKey="Rosenbohm, Christoph" sort="Rosenbohm, Christoph" uniqKey="Rosenbohm C" first="Christoph" last="Rosenbohm">Christoph Rosenbohm</name>
<name sortKey="Straarup, Ellen Marie" sort="Straarup, Ellen Marie" uniqKey="Straarup E" first="Ellen Marie" last="Straarup">Ellen Marie Straarup</name>
</noCountry>
</tree>
</affiliations>
</record>
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