Dynamic and static control of the off-target interactions of antisense oligonucleotides using toehold chemistry.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
02 Dec 2023
02 Dec 2023
Historique:
received:
12
09
2023
accepted:
17
11
2023
medline:
4
12
2023
pubmed:
3
12
2023
entrez:
2
12
2023
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 38042877
doi: 10.1038/s41467-023-43714-0
pii: 10.1038/s41467-023-43714-0
pmc: PMC10693639
doi:
Substances chimiques
Oligonucleotides, Antisense
0
RNA
63231-63-0
Peptide Nucleic Acids
0
Phosphorothioate Oligonucleotides
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
7972Subventions
Organisme : MEXT | Japan Society for the Promotion of Science (JSPS)
ID : 22H02783
Organisme : MEXT | Japan Society for the Promotion of Science (JSPS)
ID : 20H05874
Organisme : MEXT | Japan Society for the Promotion of Science (JSPS)
ID : JP22KJ2503
Organisme : MEXT | Japan Society for the Promotion of Science (JSPS)
ID : JP22J20853
Organisme : MEXT | Japan Society for the Promotion of Science (JSPS)
ID : 22H02783
Organisme : MEXT | Japan Society for the Promotion of Science (JSPS)
ID : 22H02783
Organisme : MEXT | Japan Society for the Promotion of Science (JSPS)
ID : 20H05874
Informations de copyright
© 2023. The Author(s).
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