Short locked nucleic acid antisense oligonucleotides potently reduce apolipoprotein B mRNA and serum cholesterol in mice and non-human primates
Identifieur interne : 002610 ( Main/Exploration ); précédent : 002609; suivant : 002611Short 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.
Descripteurs français
- KwdFr :
- ARN messager (métabolisme), Animaux, Apolipoprotéines B (génétique), Apolipoprotéines B (métabolisme), Autoradiographie, Cholestérol (sang), Femelle, Humains, Lignée cellulaire tumorale, Macaca fascicularis, Mésappariement de bases, Oligonucléotides (), Oligonucléotides (pharmacocinétique), Oligonucléotides (pharmacologie), Oligonucléotides antisens (), Oligonucléotides antisens (pharmacocinétique), Oligonucléotides antisens (pharmacologie), Souris, Souris de lignée C57BL.
- MESH :
- génétique : Apolipoprotéines B.
- métabolisme : ARN messager, Apolipoprotéines B.
- pharmacocinétique : Oligonucléotides, Oligonucléotides antisens.
- pharmacologie : Oligonucléotides, Oligonucléotides antisens.
- sang : Cholestérol.
- Animaux, Autoradiographie, Femelle, Humains, Lignée cellulaire tumorale, Macaca fascicularis, Mésappariement de bases, Oligonucléotides, Oligonucléotides antisens, Souris, Souris de lignée C57BL.
English descriptors
- KwdEn :
- Animals, Apolipoproteins B (genetics), Apolipoproteins B (metabolism), Autoradiography, Base Pair Mismatch, Cell Line, Tumor, Cholesterol (blood), Female, Humans, Macaca fascicularis, Mice, Mice, Inbred C57BL, Oligonucleotides (chemistry), Oligonucleotides (pharmacokinetics), Oligonucleotides (pharmacology), Oligonucleotides, Antisense (chemistry), Oligonucleotides, Antisense (pharmacokinetics), Oligonucleotides, Antisense (pharmacology), RNA, Messenger (metabolism).
- MESH :
- chemical , blood : Cholesterol.
- chemical , chemistry : Oligonucleotides, Oligonucleotides, Antisense.
- chemical , genetics : Apolipoproteins B.
- chemical , metabolism : Apolipoproteins B, RNA, Messenger.
- chemical , pharmacokinetics : Oligonucleotides, Oligonucleotides, Antisense.
- chemical , pharmacology : Oligonucleotides, Oligonucleotides, Antisense.
- Animals, Autoradiography, Base Pair Mismatch, Cell Line, Tumor, Female, Humans, Macaca fascicularis, Mice, Mice, Inbred C57BL.
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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Le document en format XML
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Lindholm</name></author><author><name sortKey="Rosenbohm, Christoph" sort="Rosenbohm, Christoph" uniqKey="Rosenbohm C" first="Christoph" last="Rosenbohm">Christoph Rosenbohm</name></author><author><name sortKey="Aarup, Vibeke" sort="Aarup, Vibeke" uniqKey="Aarup V" first="Vibeke" last="Aarup">Vibeke Aarup</name></author><author><name sortKey="Hansen, Henrik Frydenlund" sort="Hansen, Henrik Frydenlund" uniqKey="Hansen H" first="Henrik Frydenlund" last="Hansen">Henrik Frydenlund Hansen</name></author><author><name sortKey=" Rum, Henrik" sort=" Rum, Henrik" uniqKey=" Rum H" first="Henrik" last=" Rum">Henrik Rum</name></author><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></author><author><name sortKey="Koch, Troels" sort="Koch, Troels" uniqKey="Koch T" first="Troels" last="Koch">Troels Koch</name></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">20615897</idno><idno type="pmc">2978335</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2978335</idno><idno type="RBID">PMC:2978335</idno><idno type="doi">10.1093/nar/gkq457</idno><date when="2010">2010</date><idno type="wicri:Area/Pmc/Corpus">000F48</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000F48</idno><idno type="wicri:Area/Pmc/Curation">000F48</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000F48</idno><idno type="wicri:Area/Pmc/Checkpoint">001350</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">001350</idno><idno type="wicri:source">PubMed</idno><idno type="RBID">pubmed:20615897</idno><idno type="wicri:Area/PubMed/Corpus">001F47</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">001F47</idno><idno type="wicri:Area/PubMed/Curation">001F47</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">001F47</idno><idno type="wicri:Area/PubMed/Checkpoint">001E19</idno><idno type="wicri:explorRef" wicri:stream="Checkpoint" wicri:step="PubMed">001E19</idno><idno type="wicri:Area/Ncbi/Merge">000761</idno><idno type="wicri:Area/Ncbi/Curation">000761</idno><idno type="wicri:Area/Ncbi/Checkpoint">000761</idno><idno type="wicri:doubleKey">0305-1048:2010:Straarup E:short:locked:nucleic</idno><idno type="wicri:Area/Main/Merge">002635</idno><idno type="wicri:Area/Main/Curation">002610</idno><idno type="wicri:Area/Main/Exploration">002610</idno></publicationStmt><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></author><author><name sortKey="Fisker, Niels" sort="Fisker, Niels" uniqKey="Fisker N" first="Niels" last="Fisker">Niels Fisker</name></author><author><name sortKey="Hedtj Rn, Maj" sort="Hedtj Rn, Maj" uniqKey="Hedtj Rn M" first="Maj" last="Hedtj Rn">Maj Hedtj Rn</name></author><author><name sortKey="Lindholm, Marie W" sort="Lindholm, Marie W" uniqKey="Lindholm M" first="Marie W." last="Lindholm">Marie W. Lindholm</name></author><author><name sortKey="Rosenbohm, Christoph" sort="Rosenbohm, Christoph" uniqKey="Rosenbohm C" first="Christoph" last="Rosenbohm">Christoph Rosenbohm</name></author><author><name sortKey="Aarup, Vibeke" sort="Aarup, Vibeke" uniqKey="Aarup V" first="Vibeke" last="Aarup">Vibeke Aarup</name></author><author><name sortKey="Hansen, Henrik Frydenlund" sort="Hansen, Henrik Frydenlund" uniqKey="Hansen H" first="Henrik Frydenlund" last="Hansen">Henrik Frydenlund Hansen</name></author><author><name sortKey=" Rum, Henrik" sort=" Rum, Henrik" uniqKey=" Rum H" first="Henrik" last=" Rum">Henrik Rum</name></author><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></author><author><name sortKey="Koch, Troels" sort="Koch, Troels" uniqKey="Koch T" first="Troels" last="Koch">Troels Koch</name></author></analytic><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></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term><term>Apolipoproteins B (genetics)</term><term>Apolipoproteins B (metabolism)</term><term>Autoradiography</term><term>Base Pair Mismatch</term><term>Cell Line, Tumor</term><term>Cholesterol (blood)</term><term>Female</term><term>Humans</term><term>Macaca fascicularis</term><term>Mice</term><term>Mice, Inbred C57BL</term><term>Oligonucleotides (chemistry)</term><term>Oligonucleotides (pharmacokinetics)</term><term>Oligonucleotides (pharmacology)</term><term>Oligonucleotides, Antisense (chemistry)</term><term>Oligonucleotides, Antisense (pharmacokinetics)</term><term>Oligonucleotides, Antisense (pharmacology)</term><term>RNA, Messenger (metabolism)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>ARN messager (métabolisme)</term><term>Animaux</term><term>Apolipoprotéines B (génétique)</term><term>Apolipoprotéines B (métabolisme)</term><term>Autoradiographie</term><term>Cholestérol (sang)</term><term>Femelle</term><term>Humains</term><term>Lignée cellulaire tumorale</term><term>Macaca fascicularis</term><term>Mésappariement de bases</term><term>Oligonucléotides ()</term><term>Oligonucléotides (pharmacocinétique)</term><term>Oligonucléotides (pharmacologie)</term><term>Oligonucléotides antisens ()</term><term>Oligonucléotides antisens (pharmacocinétique)</term><term>Oligonucléotides antisens (pharmacologie)</term><term>Souris</term><term>Souris de lignée C57BL</term></keywords><keywords scheme="MESH" type="chemical" qualifier="blood" xml:lang="en"><term>Cholesterol</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Oligonucleotides</term><term>Oligonucleotides, Antisense</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Apolipoproteins B</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Apolipoproteins B</term><term>RNA, Messenger</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacokinetics" xml:lang="en"><term>Oligonucleotides</term><term>Oligonucleotides, Antisense</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Oligonucleotides</term><term>Oligonucleotides, Antisense</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Apolipoprotéines B</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>ARN messager</term><term>Apolipoprotéines B</term></keywords><keywords scheme="MESH" qualifier="pharmacocinétique" xml:lang="fr"><term>Oligonucléotides</term><term>Oligonucléotides antisens</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Oligonucléotides</term><term>Oligonucléotides antisens</term></keywords><keywords scheme="MESH" qualifier="sang" xml:lang="fr"><term>Cholestérol</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Autoradiography</term><term>Base Pair Mismatch</term><term>Cell Line, Tumor</term><term>Female</term><term>Humans</term><term>Macaca fascicularis</term><term>Mice</term><term>Mice, Inbred C57BL</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Animaux</term><term>Autoradiographie</term><term>Femelle</term><term>Humains</term><term>Lignée cellulaire tumorale</term><term>Macaca fascicularis</term><term>Mésappariement de bases</term><term>Oligonucléotides</term><term>Oligonucléotides antisens</term><term>Souris</term><term>Souris de lignée C57BL</term></keywords></textClass></profileDesc></teiHeader><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></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Seth, Pp" uniqKey="Seth P">PP Seth</name></author><author><name sortKey="Siwkowski, A" uniqKey="Siwkowski A">A Siwkowski</name></author><author><name sortKey="Allerson, Cr" uniqKey="Allerson C">CR Allerson</name></author><author><name sortKey="Vasquez, G" uniqKey="Vasquez G">G Vasquez</name></author><author><name sortKey="Lee, S" uniqKey="Lee S">S Lee</name></author><author><name sortKey="Prakash, Tp" uniqKey="Prakash T">TP Prakash</name></author><author><name sortKey="Wancewicz, Ev" uniqKey="Wancewicz E">EV Wancewicz</name></author><author><name sortKey="Witchell, D" uniqKey="Witchell D">D Witchell</name></author><author><name sortKey="Swayze, Ee" uniqKey="Swayze E">EE 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Tribble</name></author><author><name sortKey="Wedel, Mk" uniqKey="Wedel M">MK Wedel</name></author><author><name sortKey="Levin, Aa" uniqKey="Levin A">AA Levin</name></author><author><name sortKey="Geary, Rs" uniqKey="Geary R">RS Geary</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Schonfeld, G" uniqKey="Schonfeld G">G Schonfeld</name></author><author><name sortKey="Patterson, Bw" uniqKey="Patterson B">BW Patterson</name></author><author><name sortKey="Yablonskiy, Da" uniqKey="Yablonskiy D">DA Yablonskiy</name></author><author><name sortKey="Tanoli, Ts" uniqKey="Tanoli T">TS Tanoli</name></author><author><name sortKey="Averna, M" uniqKey="Averna M">M Averna</name></author><author><name sortKey="Elias, N" uniqKey="Elias N">N Elias</name></author><author><name sortKey="Yue, P" uniqKey="Yue P">P Yue</name></author><author><name sortKey="Ackerman, J" uniqKey="Ackerman J">J Ackerman</name></author></analytic></biblStruct></listBibl></div1></back></TEI><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>Pour manipuler ce document sous Unix (Dilib)
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