Chimeric Antisense Oligonucleotide Conjugated to α-Tocopherol
Identifieur interne : 001016 ( Ncbi/Merge ); précédent : 001015; suivant : 001017Chimeric Antisense Oligonucleotide Conjugated to α-Tocopherol
Auteurs : Tomoko Nishina [Japon] ; Junna Numata [Japon] ; Kazutaka Nishina [Japon] ; Kie Yoshida-Tanaka [Japon] ; Keiko Nitta [Japon] ; Wenying Piao [Japon] ; Rintaro Iwata [Japon] ; Shingo Ito [Japon] ; Hiroya Kuwahara [Japon] ; Takeshi Wada [Japon] ; Hidehiro Mizusawa [Japon] ; Takanori Yokota [Japon]Source :
- Molecular Therapy. Nucleic Acids [ 2162-2531 ] ; 2015.
Abstract
We developed an efficient system for delivering short interfering RNA (siRNA) to the liver by using α-tocopherol conjugation. The α-tocopherol–conjugated siRNA was effective and safe for RNA interference–mediated gene silencing
Url:
DOI: 10.1038/mtna.2014.72
PubMed: 25584900
PubMed Central: 4345304
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PMC:4345304Le document en format XML
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<author><name sortKey="Yoshida Tanaka, Kie" sort="Yoshida Tanaka, Kie" uniqKey="Yoshida Tanaka K" first="Kie" last="Yoshida-Tanaka">Kie Yoshida-Tanaka</name>
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<author><name sortKey="Nitta, Keiko" sort="Nitta, Keiko" uniqKey="Nitta K" first="Keiko" last="Nitta">Keiko Nitta</name>
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<author><name sortKey="Iwata, Rintaro" sort="Iwata, Rintaro" uniqKey="Iwata R" first="Rintaro" last="Iwata">Rintaro Iwata</name>
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<author><name sortKey="Ito, Shingo" sort="Ito, Shingo" uniqKey="Ito S" first="Shingo" last="Ito">Shingo Ito</name>
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<author><name sortKey="Kuwahara, Hiroya" sort="Kuwahara, Hiroya" uniqKey="Kuwahara H" first="Hiroya" last="Kuwahara">Hiroya Kuwahara</name>
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<author><name sortKey="Wada, Takeshi" sort="Wada, Takeshi" uniqKey="Wada T" first="Takeshi" last="Wada">Takeshi Wada</name>
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<author><name sortKey="Yokota, Takanori" sort="Yokota, Takanori" uniqKey="Yokota T" first="Takanori" last="Yokota">Takanori Yokota</name>
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<author><name sortKey="Nitta, Keiko" sort="Nitta, Keiko" uniqKey="Nitta K" first="Keiko" last="Nitta">Keiko Nitta</name>
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<author><name sortKey="Piao, Wenying" sort="Piao, Wenying" uniqKey="Piao W" first="Wenying" last="Piao">Wenying Piao</name>
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<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<author><name sortKey="Ito, Shingo" sort="Ito, Shingo" uniqKey="Ito S" first="Shingo" last="Ito">Shingo Ito</name>
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<author><name sortKey="Kuwahara, Hiroya" sort="Kuwahara, Hiroya" uniqKey="Kuwahara H" first="Hiroya" last="Kuwahara">Hiroya Kuwahara</name>
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<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<author><name sortKey="Wada, Takeshi" sort="Wada, Takeshi" uniqKey="Wada T" first="Takeshi" last="Wada">Takeshi Wada</name>
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<author><name sortKey="Mizusawa, Hidehiro" sort="Mizusawa, Hidehiro" uniqKey="Mizusawa H" first="Hidehiro" last="Mizusawa">Hidehiro Mizusawa</name>
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<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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</nlm:aff>
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<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<author><name sortKey="Yokota, Takanori" sort="Yokota, Takanori" uniqKey="Yokota T" first="Takanori" last="Yokota">Takanori Yokota</name>
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<series><title level="j">Molecular Therapy. Nucleic Acids</title>
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<front><div type="abstract" xml:lang="en"><p>We developed an efficient system for delivering short interfering RNA (siRNA) to the liver by using α-tocopherol conjugation. The α-tocopherol–conjugated siRNA was effective and safe for RNA interference–mediated gene silencing <italic>in vivo</italic>
. In contrast, when the 13-mer LNA (locked nucleic acid)-DNA gapmer antisense oligonucleotide (ASO) was directly conjugated with α-tocopherol it showed markedly reduced silencing activity in mouse liver. Here, therefore, we tried to extend the 5′-end of the ASO sequence by using 5′-α-tocopherol–conjugated 4- to 7-mers of unlocked nucleic acid (UNA) as a “second wing.” Intravenous injection of mice with this α-tocopherol–conjugated chimeric ASO achieved more potent silencing than ASO alone in the liver, suggesting increased delivery of the ASO to the liver. Within the cells, the UNA wing was cleaved or degraded and α-tocopherol was released from the 13-mer gapmer ASO, resulting in activation of the gapmer. The α-tocopherol–conjugated chimeric ASO showed high efficacy, with hepatic tropism, and was effective and safe for gene silencing <italic>in vivo</italic>
. We have thus identified a new, effective LNA-DNA gapmer structure in which drug delivery system (DDS) molecules are bound to ASO with UNA sequences.</p>
</div>
</front>
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<author><name sortKey="Altman, S" uniqKey="Altman S">S Altman</name>
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<author><name sortKey="Hari, Y" uniqKey="Hari Y">Y Hari</name>
</author>
<author><name sortKey="Morio, K" uniqKey="Morio K">K Morio</name>
</author>
<author><name sortKey="In, Y" uniqKey="In Y">Y In</name>
</author>
<author><name sortKey="Ishida, T" uniqKey="Ishida T">T Ishida</name>
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</TEI>
<double pmid="25584900"><pmc><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Chimeric Antisense Oligonucleotide Conjugated to α-Tocopherol</title>
<author><name sortKey="Nishina, Tomoko" sort="Nishina, Tomoko" uniqKey="Nishina T" first="Tomoko" last="Nishina">Tomoko Nishina</name>
<affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University</institution>
, Tokyo,<country>Japan</country>
</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST)</institution>
, Tokyo,<country>Japan</country>
</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Numata, Junna" sort="Numata, Junna" uniqKey="Numata J" first="Junna" last="Numata">Junna Numata</name>
<affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University</institution>
, Tokyo,<country>Japan</country>
</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Nishina, Kazutaka" sort="Nishina, Kazutaka" uniqKey="Nishina K" first="Kazutaka" last="Nishina">Kazutaka Nishina</name>
<affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University</institution>
, Tokyo,<country>Japan</country>
</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST)</institution>
, Tokyo,<country>Japan</country>
</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
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<affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University</institution>
, Tokyo,<country>Japan</country>
</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST)</institution>
, Tokyo,<country>Japan</country>
</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
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<affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University</institution>
, Tokyo,<country>Japan</country>
</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
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<affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University</institution>
, Tokyo,<country>Japan</country>
</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST)</institution>
, Tokyo,<country>Japan</country>
</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Iwata, Rintaro" sort="Iwata, Rintaro" uniqKey="Iwata R" first="Rintaro" last="Iwata">Rintaro Iwata</name>
<affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST)</institution>
, Tokyo,<country>Japan</country>
</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff3"><institution>Faculty of Pharmaceutical Sciences, Tokyo University of Science</institution>
, Chiba,<country>Japan</country>
</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
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<affiliation wicri:level="1"><nlm:aff id="aff4"><institution>Department of Pharmaceutical Microbiology, Kumamoto University</institution>
, Kumamoto,<country>Japan</country>
</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
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<affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University</institution>
, Tokyo,<country>Japan</country>
</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST)</institution>
, Tokyo,<country>Japan</country>
</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST)</institution>
, Tokyo,<country>Japan</country>
</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<affiliation wicri:level="1"><nlm:aff id="aff3"><institution>Faculty of Pharmaceutical Sciences, Tokyo University of Science</institution>
, Chiba,<country>Japan</country>
</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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</author>
<author><name sortKey="Mizusawa, Hidehiro" sort="Mizusawa, Hidehiro" uniqKey="Mizusawa H" first="Hidehiro" last="Mizusawa">Hidehiro Mizusawa</name>
<affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University</institution>
, Tokyo,<country>Japan</country>
</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff5"><institution>The Center for Brain Integration Research, Tokyo Medical and Dental University</institution>
, Tokyo,<country>Japan</country>
</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Yokota, Takanori" sort="Yokota, Takanori" uniqKey="Yokota T" first="Takanori" last="Yokota">Takanori Yokota</name>
<affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University</institution>
, Tokyo,<country>Japan</country>
</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST)</institution>
, Tokyo,<country>Japan</country>
</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff5"><institution>The Center for Brain Integration Research, Tokyo Medical and Dental University</institution>
, Tokyo,<country>Japan</country>
</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
</titleStmt>
<publicationStmt><idno type="wicri:source">PMC</idno>
<idno type="pmid">25584900</idno>
<idno type="pmc">4345304</idno>
<idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4345304</idno>
<idno type="RBID">PMC:4345304</idno>
<idno type="doi">10.1038/mtna.2014.72</idno>
<date when="2015">2015</date>
<idno type="wicri:Area/Pmc/Corpus">000003</idno>
<idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000003</idno>
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<idno type="wicri:Area/Pmc/Checkpoint">000E97</idno>
<idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">000E97</idno>
</publicationStmt>
<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Chimeric Antisense Oligonucleotide Conjugated to α-Tocopherol</title>
<author><name sortKey="Nishina, Tomoko" sort="Nishina, Tomoko" uniqKey="Nishina T" first="Tomoko" last="Nishina">Tomoko Nishina</name>
<affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University</institution>
, Tokyo,<country>Japan</country>
</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST)</institution>
, Tokyo,<country>Japan</country>
</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Numata, Junna" sort="Numata, Junna" uniqKey="Numata J" first="Junna" last="Numata">Junna Numata</name>
<affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University</institution>
, Tokyo,<country>Japan</country>
</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Nishina, Kazutaka" sort="Nishina, Kazutaka" uniqKey="Nishina K" first="Kazutaka" last="Nishina">Kazutaka Nishina</name>
<affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University</institution>
, Tokyo,<country>Japan</country>
</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST)</institution>
, Tokyo,<country>Japan</country>
</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Yoshida Tanaka, Kie" sort="Yoshida Tanaka, Kie" uniqKey="Yoshida Tanaka K" first="Kie" last="Yoshida-Tanaka">Kie Yoshida-Tanaka</name>
<affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University</institution>
, Tokyo,<country>Japan</country>
</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST)</institution>
, Tokyo,<country>Japan</country>
</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Nitta, Keiko" sort="Nitta, Keiko" uniqKey="Nitta K" first="Keiko" last="Nitta">Keiko Nitta</name>
<affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University</institution>
, Tokyo,<country>Japan</country>
</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Piao, Wenying" sort="Piao, Wenying" uniqKey="Piao W" first="Wenying" last="Piao">Wenying Piao</name>
<affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University</institution>
, Tokyo,<country>Japan</country>
</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST)</institution>
, Tokyo,<country>Japan</country>
</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Iwata, Rintaro" sort="Iwata, Rintaro" uniqKey="Iwata R" first="Rintaro" last="Iwata">Rintaro Iwata</name>
<affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST)</institution>
, Tokyo,<country>Japan</country>
</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff3"><institution>Faculty of Pharmaceutical Sciences, Tokyo University of Science</institution>
, Chiba,<country>Japan</country>
</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Ito, Shingo" sort="Ito, Shingo" uniqKey="Ito S" first="Shingo" last="Ito">Shingo Ito</name>
<affiliation wicri:level="1"><nlm:aff id="aff4"><institution>Department of Pharmaceutical Microbiology, Kumamoto University</institution>
, Kumamoto,<country>Japan</country>
</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Kuwahara, Hiroya" sort="Kuwahara, Hiroya" uniqKey="Kuwahara H" first="Hiroya" last="Kuwahara">Hiroya Kuwahara</name>
<affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University</institution>
, Tokyo,<country>Japan</country>
</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST)</institution>
, Tokyo,<country>Japan</country>
</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Wada, Takeshi" sort="Wada, Takeshi" uniqKey="Wada T" first="Takeshi" last="Wada">Takeshi Wada</name>
<affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST)</institution>
, Tokyo,<country>Japan</country>
</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff3"><institution>Faculty of Pharmaceutical Sciences, Tokyo University of Science</institution>
, Chiba,<country>Japan</country>
</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Mizusawa, Hidehiro" sort="Mizusawa, Hidehiro" uniqKey="Mizusawa H" first="Hidehiro" last="Mizusawa">Hidehiro Mizusawa</name>
<affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University</institution>
, Tokyo,<country>Japan</country>
</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff5"><institution>The Center for Brain Integration Research, Tokyo Medical and Dental University</institution>
, Tokyo,<country>Japan</country>
</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Yokota, Takanori" sort="Yokota, Takanori" uniqKey="Yokota T" first="Takanori" last="Yokota">Takanori Yokota</name>
<affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University</institution>
, Tokyo,<country>Japan</country>
</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST)</institution>
, Tokyo,<country>Japan</country>
</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff5"><institution>The Center for Brain Integration Research, Tokyo Medical and Dental University</institution>
, Tokyo,<country>Japan</country>
</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
</analytic>
<series><title level="j">Molecular Therapy. Nucleic Acids</title>
<idno type="eISSN">2162-2531</idno>
<imprint><date when="2015">2015</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass></textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en"><p>We developed an efficient system for delivering short interfering RNA (siRNA) to the liver by using α-tocopherol conjugation. The α-tocopherol–conjugated siRNA was effective and safe for RNA interference–mediated gene silencing <italic>in vivo</italic>
. In contrast, when the 13-mer LNA (locked nucleic acid)-DNA gapmer antisense oligonucleotide (ASO) was directly conjugated with α-tocopherol it showed markedly reduced silencing activity in mouse liver. Here, therefore, we tried to extend the 5′-end of the ASO sequence by using 5′-α-tocopherol–conjugated 4- to 7-mers of unlocked nucleic acid (UNA) as a “second wing.” Intravenous injection of mice with this α-tocopherol–conjugated chimeric ASO achieved more potent silencing than ASO alone in the liver, suggesting increased delivery of the ASO to the liver. Within the cells, the UNA wing was cleaved or degraded and α-tocopherol was released from the 13-mer gapmer ASO, resulting in activation of the gapmer. The α-tocopherol–conjugated chimeric ASO showed high efficacy, with hepatic tropism, and was effective and safe for gene silencing <italic>in vivo</italic>
. We have thus identified a new, effective LNA-DNA gapmer structure in which drug delivery system (DDS) molecules are bound to ASO with UNA sequences.</p>
</div>
</front>
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<pubmed><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Chimeric Antisense Oligonucleotide Conjugated to α-Tocopherol.</title>
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<country xml:lang="fr">Japon</country>
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<author><name sortKey="Numata, Junna" sort="Numata, Junna" uniqKey="Numata J" first="Junna" last="Numata">Junna Numata</name>
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<wicri:regionArea>Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University, Tokyo</wicri:regionArea>
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<author><name sortKey="Nishina, Kazutaka" sort="Nishina, Kazutaka" uniqKey="Nishina K" first="Kazutaka" last="Nishina">Kazutaka Nishina</name>
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<country xml:lang="fr">Japon</country>
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<author><name sortKey="Yoshida Tanaka, Kie" sort="Yoshida Tanaka, Kie" uniqKey="Yoshida Tanaka K" first="Kie" last="Yoshida-Tanaka">Kie Yoshida-Tanaka</name>
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<country xml:lang="fr">Japon</country>
<wicri:regionArea>1] Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan [2] Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Tokyo</wicri:regionArea>
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<author><name sortKey="Nitta, Keiko" sort="Nitta, Keiko" uniqKey="Nitta K" first="Keiko" last="Nitta">Keiko Nitta</name>
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<author><name sortKey="Piao, Wenying" sort="Piao, Wenying" uniqKey="Piao W" first="Wenying" last="Piao">Wenying Piao</name>
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<country xml:lang="fr">Japon</country>
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<sourceDesc><biblStruct><analytic><title xml:lang="en">Chimeric Antisense Oligonucleotide Conjugated to α-Tocopherol.</title>
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<country xml:lang="fr">Japon</country>
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<author><name sortKey="Numata, Junna" sort="Numata, Junna" uniqKey="Numata J" first="Junna" last="Numata">Junna Numata</name>
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</affiliation>
</author>
<author><name sortKey="Nishina, Kazutaka" sort="Nishina, Kazutaka" uniqKey="Nishina K" first="Kazutaka" last="Nishina">Kazutaka Nishina</name>
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<country xml:lang="fr">Japon</country>
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<author><name sortKey="Yoshida Tanaka, Kie" sort="Yoshida Tanaka, Kie" uniqKey="Yoshida Tanaka K" first="Kie" last="Yoshida-Tanaka">Kie Yoshida-Tanaka</name>
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<country xml:lang="fr">Japon</country>
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<author><name sortKey="Nitta, Keiko" sort="Nitta, Keiko" uniqKey="Nitta K" first="Keiko" last="Nitta">Keiko Nitta</name>
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<author><name sortKey="Piao, Wenying" sort="Piao, Wenying" uniqKey="Piao W" first="Wenying" last="Piao">Wenying Piao</name>
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<country xml:lang="fr">Japon</country>
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<author><name sortKey="Iwata, Rintaro" sort="Iwata, Rintaro" uniqKey="Iwata R" first="Rintaro" last="Iwata">Rintaro Iwata</name>
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<author><name sortKey="Ito, Shingo" sort="Ito, Shingo" uniqKey="Ito S" first="Shingo" last="Ito">Shingo Ito</name>
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<author><name sortKey="Kuwahara, Hiroya" sort="Kuwahara, Hiroya" uniqKey="Kuwahara H" first="Hiroya" last="Kuwahara">Hiroya Kuwahara</name>
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<country xml:lang="fr">Japon</country>
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<placeName><settlement type="city">Tokyo</settlement>
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<author><name sortKey="Wada, Takeshi" sort="Wada, Takeshi" uniqKey="Wada T" first="Takeshi" last="Wada">Takeshi Wada</name>
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<country xml:lang="fr">Japon</country>
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</author>
<author><name sortKey="Mizusawa, Hidehiro" sort="Mizusawa, Hidehiro" uniqKey="Mizusawa H" first="Hidehiro" last="Mizusawa">Hidehiro Mizusawa</name>
<affiliation wicri:level="3"><nlm:affiliation>1] Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan [2] The Center for Brain Integration Research, Tokyo Medical and Dental University, Tokyo, Japan.</nlm:affiliation>
<country xml:lang="fr">Japon</country>
<wicri:regionArea>1] Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan [2] The Center for Brain Integration Research, Tokyo Medical and Dental University, Tokyo</wicri:regionArea>
<placeName><settlement type="city">Tokyo</settlement>
<region type="région">Région de Kantō</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Yokota, Takanori" sort="Yokota, Takanori" uniqKey="Yokota T" first="Takanori" last="Yokota">Takanori Yokota</name>
<affiliation wicri:level="3"><nlm:affiliation>1] Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan [2] Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Tokyo, Japan [3] The Center for Brain Integration Research, Tokyo Medical and Dental University, Tokyo, Japan.</nlm:affiliation>
<country xml:lang="fr">Japon</country>
<wicri:regionArea>1] Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan [2] Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Tokyo, Japan [3] The Center for Brain Integration Research, Tokyo Medical and Dental University, Tokyo</wicri:regionArea>
<placeName><settlement type="city">Tokyo</settlement>
<region type="région">Région de Kantō</region>
</placeName>
</affiliation>
</author>
</analytic>
<series><title level="j">Molecular therapy. Nucleic acids</title>
<idno type="ISSN">2162-2531</idno>
<imprint><date when="2015" type="published">2015</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass></textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en">We developed an efficient system for delivering short interfering RNA (siRNA) to the liver by using α-tocopherol conjugation. The α-tocopherol-conjugated siRNA was effective and safe for RNA interference-mediated gene silencing in vivo. In contrast, when the 13-mer LNA (locked nucleic acid)-DNA gapmer antisense oligonucleotide (ASO) was directly conjugated with α-tocopherol it showed markedly reduced silencing activity in mouse liver. Here, therefore, we tried to extend the 5'-end of the ASO sequence by using 5'-α-tocopherol-conjugated 4- to 7-mers of unlocked nucleic acid (UNA) as a "second wing." Intravenous injection of mice with this α-tocopherol-conjugated chimeric ASO achieved more potent silencing than ASO alone in the liver, suggesting increased delivery of the ASO to the liver. Within the cells, the UNA wing was cleaved or degraded and α-tocopherol was released from the 13-mer gapmer ASO, resulting in activation of the gapmer. The α-tocopherol-conjugated chimeric ASO showed high efficacy, with hepatic tropism, and was effective and safe for gene silencing in vivo. We have thus identified a new, effective LNA-DNA gapmer structure in which drug delivery system (DDS) molecules are bound to ASO with UNA sequences. </div>
</front>
</TEI>
</pubmed>
</double>
</record>
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