Identification of nucleobase chemical modifications that reduce the hepatotoxicity of gapmer antisense oligonucleotides.
Journal
Nucleic acids research
ISSN: 1362-4962
Titre abrégé: Nucleic Acids Res
Pays: England
ID NLM: 0411011
Informations de publication
Date de publication:
22 07 2022
22 07 2022
Historique:
accepted:
23
06
2022
revised:
30
05
2022
received:
22
06
2021
pubmed:
9
7
2022
medline:
26
7
2022
entrez:
8
7
2022
Statut:
ppublish
Résumé
Currently, gapmer antisense oligonucleotide (ASO) therapeutics are under clinical development for the treatment of various diseases, including previously intractable human disorders; however, they have the potential to induce hepatotoxicity. Although several groups have reported the reduced hepatotoxicity of gapmer ASOs following chemical modifications of sugar residues or internucleotide linkages, only few studies have described nucleobase modifications to reduce hepatotoxicity. In this study, we introduced single or multiple combinations of 17 nucleobase derivatives, including four novel derivatives, into hepatotoxic locked nucleic acid gapmer ASOs and examined their effects on hepatotoxicity. The results demonstrated successful identification of chemical modifications that strongly reduced the hepatotoxicity of gapmer ASOs. This approach expands the ability to design gapmer ASOs with optimal therapeutic profiles.
Identifiants
pubmed: 35801870
pii: 6633893
doi: 10.1093/nar/gkac562
pmc: PMC9303313
doi:
Substances chimiques
Oligonucleotides, Antisense
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
7224-7234Informations de copyright
© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.
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