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2′-OMe-phosphorodithioate-modified siRNAs show increased loading into the RISC complex and enhanced anti-tumour activity

Author

Listed:
  • Sherry Y. Wu

    (The University of Texas MD Anderson Cancer Center (MDACC))

  • Xianbin Yang

    (AM Biotechnologies LLC, 12521 Gulf Freeway)

  • Kshipra M. Gharpure

    (The University of Texas MD Anderson Cancer Center (MDACC))

  • Hiroto Hatakeyama

    (The University of Texas MD Anderson Cancer Center (MDACC))

  • Martin Egli

    (Vanderbilt University, School of Medicine)

  • Michael H. McGuire

    (The University of Texas MD Anderson Cancer Center (MDACC))

  • Archana S. Nagaraja

    (The University of Texas MD Anderson Cancer Center (MDACC))

  • Takahito M. Miyake

    (The University of Texas MD Anderson Cancer Center (MDACC))

  • Rajesha Rupaimoole

    (The University of Texas MD Anderson Cancer Center (MDACC))

  • Chad V. Pecot

    (MDACC)

  • Morgan Taylor

    (The University of Texas MD Anderson Cancer Center (MDACC))

  • Sunila Pradeep

    (The University of Texas MD Anderson Cancer Center (MDACC))

  • Malgorzata Sierant

    (Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences)

  • Cristian Rodriguez-Aguayo

    (MDACC
    Center for RNA Interference and Non-Coding RNA, MDACC)

  • Hyun J. Choi

    (The University of Texas MD Anderson Cancer Center (MDACC))

  • Rebecca A. Previs

    (The University of Texas MD Anderson Cancer Center (MDACC))

  • Guillermo N. Armaiz-Pena

    (The University of Texas MD Anderson Cancer Center (MDACC))

  • Li Huang

    (MDACC)

  • Carlos Martinez

    (Sigma Life Science)

  • Tom Hassell

    (Sigma Life Science)

  • Cristina Ivan

    (The University of Texas MD Anderson Cancer Center (MDACC)
    Center for RNA Interference and Non-Coding RNA, MDACC)

  • Vasudha Sehgal

    (MDACC)

  • Richa Singhania

    (University of Queensland Diamantina Institute
    Centre for Biomolecular Sciences, School of Pharmacy, The University of Nottingham)

  • Hee-Dong Han

    (The University of Texas MD Anderson Cancer Center (MDACC)
    Center for RNA Interference and Non-Coding RNA, MDACC
    School of Medicine, Konkuk University)

  • Chang Su

    (The University of Texas MD Anderson Cancer Center (MDACC))

  • Ji Hoon Kim

    (MDACC
    Korea University College of Medicine)

  • Heather J. Dalton

    (The University of Texas MD Anderson Cancer Center (MDACC))

  • Chandra Kovvali

    (The University of Texas MD Anderson Cancer Center (MDACC))

  • Khandan Keyomarsi

    (MDACC)

  • Nigel A. J. McMillan

    (University of Queensland Diamantina Institute
    Griffith Health Institute and School of Medical Sciences, Griffith University)

  • Willem W. Overwijk

    (MDACC)

  • Jinsong Liu

    (MDACC)

  • Ju-Seog Lee

    (MDACC)

  • Keith A. Baggerly

    (MDACC)

  • Gabriel Lopez-Berestein

    (MDACC
    Center for RNA Interference and Non-Coding RNA, MDACC)

  • Prahlad T. Ram

    (MDACC)

  • Barbara Nawrot

    (Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences)

  • Anil K. Sood

    (The University of Texas MD Anderson Cancer Center (MDACC)
    Center for RNA Interference and Non-Coding RNA, MDACC
    MDACC)

Abstract

Improving small interfering RNA (siRNA) efficacy in target cell populations remains a challenge to its clinical implementation. Here, we report a chemical modification, consisting of phosphorodithioate (PS2) and 2′-O-Methyl (2′-OMe) MePS2 on one nucleotide that significantly enhances potency and resistance to degradation for various siRNAs. We find enhanced potency stems from an unforeseen increase in siRNA loading to the RNA-induced silencing complex, likely due to the unique interaction mediated by 2′-OMe and PS2. We demonstrate the therapeutic utility of MePS2 siRNAs in chemoresistant ovarian cancer mouse models via targeting GRAM domain containing 1B (GRAMD1B), a protein involved in chemoresistance. GRAMD1B silencing is achieved in tumours following MePS2-modified siRNA treatment, leading to a synergistic anti-tumour effect in combination with paclitaxel. Given the previously limited success in enhancing siRNA potency with chemically modified siRNAs, our findings represent an important advance in siRNA design with the potential for application in numerous cancer types.

Suggested Citation

  • Sherry Y. Wu & Xianbin Yang & Kshipra M. Gharpure & Hiroto Hatakeyama & Martin Egli & Michael H. McGuire & Archana S. Nagaraja & Takahito M. Miyake & Rajesha Rupaimoole & Chad V. Pecot & Morgan Taylor, 2014. "2′-OMe-phosphorodithioate-modified siRNAs show increased loading into the RISC complex and enhanced anti-tumour activity," Nature Communications, Nature, vol. 5(1), pages 1-12, May.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms4459
    DOI: 10.1038/ncomms4459
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