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

Associate Professor Tsuyoshi Yamamoto and his research group in the Department of Chemistry of Biofunctional Molecules, Graduate School of Biomedical Sciences, Nagasaki University have successfully reduced the side effects of ASO drugs by leveraging thermodynamics.

■Research 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.


■Journal Information  
Journal: Nature Communications
Title: Dynamic and static control of the off-target interactions of antisense oligonucleotides using toehold chemistry
Author information: Chisato Terada, Kaho Oh, Ryutaro Tsubaki, Bun Chan, Nozomi Aibara, Kaname Ohyama, Masa-Aki Shibata, Takehiko Wada, Mariko Harada-Shiba, Asako Yamayoshi, Tsuyoshi Yamamoto
DOI: https://doi.org/10.1038/s41467-023-43714-0
Published: 02 December 2023


This release is also available in Japanese

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