Molecular therapy : the journal of the American Society of Gene Therapy · 2023
Use of 2,6-diaminopurine as a potent suppressor of UGA premature stop codons in cystic fibrosis.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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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
Аннотация
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.