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Chimeric Antisense Oligonucleotide Conjugated to α-Tocopherol

Identifieur interne : 001867 ( Main/Exploration ); précédent : 001866; suivant : 001868

Chimeric 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 :

RBID : PMC:4345304

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 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.


Url:
DOI: 10.1038/mtna.2014.72
PubMed: 25584900
PubMed Central: 4345304


Affiliations:


Links toward previous steps (curation, corpus...)


Le document en format XML

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<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<title level="j">Molecular Therapy. Nucleic Acids</title>
<idno type="eISSN">2162-2531</idno>
<imprint>
<date when="2015">2015</date>
</imprint>
</series>
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<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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</TEI>
<affiliations>
<list>
<country>
<li>Japon</li>
</country>
</list>
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<country name="Japon">
<noRegion>
<name sortKey="Nishina, Tomoko" sort="Nishina, Tomoko" uniqKey="Nishina T" first="Tomoko" last="Nishina">Tomoko Nishina</name>
</noRegion>
<name sortKey="Ito, Shingo" sort="Ito, Shingo" uniqKey="Ito S" first="Shingo" last="Ito">Shingo Ito</name>
<name sortKey="Iwata, Rintaro" sort="Iwata, Rintaro" uniqKey="Iwata R" first="Rintaro" last="Iwata">Rintaro Iwata</name>
<name sortKey="Iwata, Rintaro" sort="Iwata, Rintaro" uniqKey="Iwata R" first="Rintaro" last="Iwata">Rintaro Iwata</name>
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<name sortKey="Yokota, Takanori" sort="Yokota, Takanori" uniqKey="Yokota T" first="Takanori" last="Yokota">Takanori Yokota</name>
<name sortKey="Yokota, Takanori" sort="Yokota, Takanori" uniqKey="Yokota T" first="Takanori" last="Yokota">Takanori Yokota</name>
<name sortKey="Yokota, Takanori" sort="Yokota, Takanori" uniqKey="Yokota T" first="Takanori" last="Yokota">Takanori Yokota</name>
<name sortKey="Yoshida Tanaka, Kie" sort="Yoshida Tanaka, Kie" uniqKey="Yoshida Tanaka K" first="Kie" last="Yoshida-Tanaka">Kie Yoshida-Tanaka</name>
<name sortKey="Yoshida Tanaka, Kie" sort="Yoshida Tanaka, Kie" uniqKey="Yoshida Tanaka K" first="Kie" last="Yoshida-Tanaka">Kie Yoshida-Tanaka</name>
</country>
</tree>
</affiliations>
</record>

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Pour mettre un lien sur cette page dans le réseau Wicri

{{Explor lien
   |wiki=    Sante
   |area=    MersV1
   |flux=    Main
   |étape=   Exploration
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   |clé=     PMC:4345304
   |texte=   Chimeric Antisense Oligonucleotide Conjugated to α-Tocopherol
}}

Pour générer des pages wiki

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Data generation: Mon Apr 20 23:26:43 2020. Site generation: Sat Mar 27 09:06:09 2021