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DNA/RNA heteroduplex oligonucleotide for highly efficient gene silencing

Author

Listed:
  • Kazutaka Nishina

    (Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan
    Section of Molecular Technology, Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST))

  • Wenying Piao

    (Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan
    Section of Molecular Technology, Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST))

  • Kie Yoshida-Tanaka

    (Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan
    Section of Molecular Technology, Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST))

  • Yumiko Sujino

    (Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan
    Section of Molecular Technology, Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST))

  • Tomoko Nishina

    (Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan
    Section of Molecular Technology, Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST))

  • Tsuyoshi Yamamoto

    (Bioorganic Chemistry, Graduate School of Pharmaceutical Sciences, Osaka University)

  • Keiko Nitta

    (Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan)

  • Kotaro Yoshioka

    (Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan
    Section of Molecular Technology, Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST))

  • Hiroya Kuwahara

    (Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan
    Section of Molecular Technology, Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST))

  • Hidenori Yasuhara

    (Bioorganic Chemistry, Graduate School of Pharmaceutical Sciences, Osaka University)

  • Takeshi Baba

    (Bioorganic Chemistry, Graduate School of Pharmaceutical Sciences, Osaka University)

  • Fumiko Ono

    (The Corporation for Production and Research of Laboratory Primates, 1-16-2 Sakura, Tsukuba-shi, Ibaraki 305-0003, Japan)

  • Kanjiro Miyata

    (Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan)

  • Koichi Miyake

    (Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan)

  • Punit P. Seth

    (Isis Pharmaceuticals)

  • Audrey Low

    (Isis Pharmaceuticals)

  • Masayuki Yoshida

    (Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan)

  • C. Frank Bennett

    (Isis Pharmaceuticals)

  • Kazunori Kataoka

    (Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
    Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan)

  • Hidehiro Mizusawa

    (Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan)

  • Satoshi Obika

    (Section of Molecular Technology, Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST)
    Bioorganic Chemistry, Graduate School of Pharmaceutical Sciences, Osaka University)

  • Takanori Yokota

    (Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan
    Section of Molecular Technology, Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST))

Abstract

Antisense oligonucleotides (ASOs) are recognized therapeutic agents for the modulation of specific genes at the post-transcriptional level. Similar to any medical drugs, there are opportunities to improve their efficacy and safety. Here we develop a short DNA/RNA heteroduplex oligonucleotide (HDO) with a structure different from double-stranded RNA used for short interfering RNA and single-stranded DNA used for ASO. A DNA/locked nucleotide acid gapmer duplex with an α-tocopherol-conjugated complementary RNA (Toc-HDO) is significantly more potent at reducing the expression of the targeted mRNA in liver compared with the parent single-stranded gapmer ASO. Toc-HDO also improves the phenotype in disease models more effectively. In addition, the high potency of Toc-HDO results in a reduction of liver dysfunction observed in the parent ASO at a similar silencing effect. HDO technology offers a novel concept of therapeutic oligonucleotides, and the development of this molecular design opens a new therapeutic field.

Suggested Citation

  • Kazutaka Nishina & Wenying Piao & Kie Yoshida-Tanaka & Yumiko Sujino & Tomoko Nishina & Tsuyoshi Yamamoto & Keiko Nitta & Kotaro Yoshioka & Hiroya Kuwahara & Hidenori Yasuhara & Takeshi Baba & Fumiko , 2015. "DNA/RNA heteroduplex oligonucleotide for highly efficient gene silencing," Nature Communications, Nature, vol. 6(1), pages 1-13, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms8969
    DOI: 10.1038/ncomms8969
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    Cited by:

    1. Juri Hasegawa & Tetsuya Nagata & Kensuke Ihara & Jun Tanihata & Satoe Ebihara & Kie Yoshida-Tanaka & Mitsugu Yanagidaira & Masahiro Ohara & Asuka Sasaki & Miyu Nakayama & Syunsuke Yamamoto & Takashi I, 2024. "Heteroduplex oligonucleotide technology boosts oligonucleotide splice switching activity of morpholino oligomers in a Duchenne muscular dystrophy mouse model," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

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