Use of 2,6-diaminopurine as a potent suppressor of UGA premature stop codons in cystic fibrosis
Leroy, Catherine; Spelier, Sacha; Essonghe, Nadège Charlene; Poix, Virginie; Kong, Rebekah; Gizzi, Patrick; Bourban, Claire; Amand, Séverine; Bailly, Christine; Guilbert, Romain; Hannebique, David; Persoons, Philippe; Arhant, Gwenaëlle; Prévotat, Anne; Reix, Philippe; Hubert, Dominique; Gérardin, Michèle; Chamaillard, Mathias; Prevarskaya, Natalia; Rebuffat, Sylvie; Shapovalov, George; Beekman, Jeffrey; Lejeune, Fabrice
(2023) Molecular Therapy, volume 31, issue 4, pp. 970 - 985
(Article)
Abstract
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
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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.
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Keywords: 2,6-diaminopurine, cystic fibrosis, mouse model, nonsense mutation, readthrough molecule, Molecular Medicine, Molecular Biology, Genetics, Pharmacology, Drug Discovery
ISSN: 1525-0016
Publisher: Cell Press
Note: Funding Information: The authors would like to thank Dr. Anne Tsicopoulos and Dr. Quentin Thommen for helpful discussions and advice on IHC and statistical analysis. The authors would also like to deeply thank the Cystic Fibrosis Foundation, for the donation of 16HBE14o− cells carrying nonsense mutations, and Professor Dieter Gruenert for the donation of 16HBE14o− WT cells. F.L. is supported by funding from Vaincre la Mucoviscidose , the Association Française contre les Myopathies , the Agence Nationale de la Recherche , the Fondation Les Ailes , and the Fondation Maladies Rares . Canther Laboratory is part of ONCOLille Institute. This work is supported by a grant from Contrat de Plan Etat-Région CPER Cancer 2015–2020. Funding Information: The authors would like to thank Dr. Anne Tsicopoulos and Dr. Quentin Thommen for helpful discussions and advice on IHC and statistical analysis. The authors would also like to deeply thank the Cystic Fibrosis Foundation, for the donation of 16HBE14o− cells carrying nonsense mutations, and Professor Dieter Gruenert for the donation of 16HBE14o− WT cells. F.L. is supported by funding from Vaincre la Mucoviscidose, the Association Française contre les Myopathies, the Agence Nationale de la Recherche, the Fondation Les Ailes, and the Fondation Maladies Rares. Canther Laboratory is part of ONCOLille Institute. This work is supported by a grant from Contrat de Plan Etat-Région CPER Cancer 2015–2020. Conceptualization, C.L. S.S. J.B. G.S. and F.L.; methodology, C.L. S.S. N.C.E. V.P. R.K. P.G. S.A. and C. Bailly; investigation, C.L. S.S. V.P. N.C.E. R.K. P.G. S.A. C. Bourban and C. Bailly; funding acquisition, N.P. J.B. and F.L.; project administration, F.L.; supervision, P.G. S.A. C. Bailly, D. Hannebique, A.P. P.R. D. Hubert, M.G. M.C. S.R. J.B. and F.L.; writing – original draft, C.L. S.S. G.S. and F.L.; writing – review & editing, all authors. 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. Publisher Copyright: © 2023 The Authors
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