Dynamic and static control of the off-target interactions of antisense oligonucleotides using toehold chemistry
In: Nat Commun, 2023
academicJournal
Zugriff:
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.
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Dynamic and static control of the off-target interactions of antisense oligonucleotides using toehold chemistry
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Autor/in / Beteiligte Person: | Terada, Chisato ; Oh, Kaho ; Tsubaki, Ryutaro ; Chan, Bun ; Aibara, Nozomi ; Ohyama, Kaname ; Shibata, Masa-Aki ; Wada, Takehiko ; Harada-Shiba, Mariko ; Yamayoshi, Asako ; Yamamoto, Tsuyoshi |
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Zeitschrift: | Nat Commun, 2023 |
Veröffentlichung: | Nature Publishing Group UK, 2023 |
Medientyp: | academicJournal |
DOI: | 10.1038/s41467-023-43714-0 |
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