Use of 2,6-diaminopurine as a potent suppressor of UGA premature stop codons in cystic fibrosis.
2,6-diaminopurine
cystic fibrosis
mouse model
nonsense mutation
readthrough molecule
Journal
Molecular therapy : the journal of the American Society of Gene Therapy
ISSN: 1525-0024
Titre abrégé: Mol Ther
Pays: United States
ID NLM: 100890581
Informations de publication
Date de publication:
05 04 2023
05 04 2023
Historique:
received:
25
07
2022
revised:
10
12
2022
accepted:
12
01
2023
pmc-release:
05
04
2024
medline:
10
4
2023
pubmed:
16
1
2023
entrez:
15
1
2023
Statut:
ppublish
Résumé
Nonsense mutations are responsible for around 10% of cases of genetic diseases, including cystic fibrosis. 2,6-diaminopurine (DAP) has recently been shown to promote efficient readthrough of UGA premature stop codons. In this study, we show that DAP can correct a nonsense mutation in the Cftr gene in vivo in a new CF mouse model, in utero, and through breastfeeding, thanks, notably, to adequate pharmacokinetic properties. DAP turns out to be very stable in plasma and is distributed throughout the body. The ability of DAP to correct various endogenous UGA nonsense mutations in the CFTR gene and to restore its function in mice, in organoids derived from murine or patient cells, and in cells from patients with cystic fibrosis reveals the potential of such readthrough-stimulating molecules in developing a therapeutic approach. The fact that correction by DAP of certain nonsense mutations reaches a clinically relevant level, as judged from previous studies, makes the use of this compound all the more attractive.
Identifiants
pubmed: 36641622
pii: S1525-0016(23)00014-X
doi: 10.1016/j.ymthe.2023.01.014
pmc: PMC10124085
pii:
doi:
Substances chimiques
Codon, Nonsense
0
Codon, Terminator
0
Cystic Fibrosis Transmembrane Conductance Regulator
126880-72-6
2,6-diaminopurine
49P95BAU4Z
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
970-985Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests J.B. is inventor on a patent related to the FIS assay and received financial royalties from 2017 onward. S.A., C. Bailly, S.R., and F.L. are inventors on a patent demonstrating that DAP is a readthrough molecule useful for the treatment of genetic diseases related to nonsense mutations.
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