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Chimeric Antisense Oligonucleotide Conjugated to α-Tocopherol.
Nishina, Tomoko; Numata, Junna; Nishina, Kazutaka; Yoshida-Tanaka, Kie; Nitta, Keiko; Piao, Wenying; Iwata, Rintaro; Ito, Shingo; Kuwahara, Hiroya; Wada, Takeshi; Mizusawa, Hidehiro; Yokota, Takanori.
Afiliação
  • Nishina T; 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.
  • Numata J; Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
  • Nishina K; 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.
  • Yoshida-Tanaka K; 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.
  • Nitta K; Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
  • Piao W; 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.
  • Iwata R; 1] Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Tokyo, Japan [2] Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba, Japan.
  • Ito S; Department of Pharmaceutical Microbiology, Kumamoto University, Kumamoto, Japan.
  • Kuwahara H; 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.
  • Wada T; 1] Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Tokyo, Japan [2] Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba, Japan.
  • Mizusawa H; 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.
  • Yokota T; 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 Medic
Mol Ther Nucleic Acids ; 4: e220, 2015 Jan 13.
Article em En | MEDLINE | ID: mdl-25584900
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.

Texto completo: 1 Base de dados: MEDLINE Idioma: En Revista: Mol Ther Nucleic Acids Ano de publicação: 2015 Tipo de documento: Article País de afiliação: Japão

Texto completo: 1 Base de dados: MEDLINE Idioma: En Revista: Mol Ther Nucleic Acids Ano de publicação: 2015 Tipo de documento: Article País de afiliação: Japão