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Dynamic and static control of the off-target interactions of antisense oligonucleotides using toehold chemistry

Author

Listed:
  • Chisato Terada

    (Nagasaki University
    Japan Society for the Promotion of Science)

  • Kaho Oh

    (Nagasaki University)

  • Ryutaro Tsubaki

    (Nagasaki University)

  • Bun Chan

    (Nagasaki University)

  • Nozomi Aibara

    (Nagasaki University)

  • Kaname Ohyama

    (Nagasaki University)

  • Masa-Aki Shibata

    (Osaka Medical and Pharmaceutical University)

  • Takehiko Wada

    (Tohoku University)

  • Mariko Harada-Shiba

    (National Cerebral and Cardiovascular Center Research Institute
    Osaka Medical and Pharmaceutical University)

  • Asako Yamayoshi

    (Nagasaki University)

  • Tsuyoshi Yamamoto

    (Nagasaki University)

Abstract

Off-target interactions between antisense oligonucleotides (ASOs) with state-of-the-art modifications and biological components still pose clinical safety liabilities. To mitigate a broad spectrum of off-target interactions and enhance the safety profile of ASO drugs, we here devise a nanoarchitecture named BRace On a THERapeutic aSo (BROTHERS or BRO), which is composed of a standard gapmer ASO paired with a partially complementary peptide nucleic acid (PNA) strand. We show that these non-canonical ASO/PNA hybrids have reduced non-specific protein-binding capacity. The optimization of the structural and thermodynamic characteristics of this duplex system enables the operation of an in vivo toehold-mediated strand displacement (TMSD) reaction, effectively reducing hybridization with RNA off-targets. The optimized BROs dramatically mitigate hepatotoxicity while maintaining the on-target knockdown activity of their parent ASOs in vivo. This technique not only introduces a BRO class of drugs that could have a transformative impact on the extrahepatic delivery of ASOs, but can also help uncover the toxicity mechanism of ASOs.

Suggested Citation

  • Chisato Terada & Kaho Oh & Ryutaro Tsubaki & Bun Chan & Nozomi Aibara & Kaname Ohyama & Masa-Aki Shibata & Takehiko Wada & Mariko Harada-Shiba & Asako Yamayoshi & Tsuyoshi Yamamoto, 2023. "Dynamic and static control of the off-target interactions of antisense oligonucleotides using toehold chemistry," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-43714-0
    DOI: 10.1038/s41467-023-43714-0
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    References listed on IDEAS

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    1. Robert R. F. Machinek & Thomas E. Ouldridge & Natalie E. C. Haley & Jonathan Bath & Andrew J. Turberfield, 2014. "Programmable energy landscapes for kinetic control of DNA strand displacement," Nature Communications, Nature, vol. 5(1), pages 1-9, December.
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