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

Chisato Terada, Kaho Oh, Ryutaro Tsubaki, Bun Chan, Nozomi Aibara, Kaname Ohyama, Masa-Aki Shibata, Takehiko Wada, Mariko Harada-Shiba, Asako Yamayoshi and Tsuyoshi Yamamoto ()
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Chisato Terada: Nagasaki University
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
Asako Yamayoshi: Nagasaki University
Tsuyoshi Yamamoto: Nagasaki University

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-43714-0

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