2. Academic Validation
  3. Use of 2,6-diaminopurine as a potent suppressor of UGA premature stop codons in cystic fibrosis

Use of 2,6-diaminopurine as a potent suppressor of UGA premature stop codons in cystic fibrosis

  • Mol Ther. 2023 Jan 13;S1525-0016(23)00014-X. doi: 10.1016/j.ymthe.2023.01.014.
Catherine Leroy 1,  Sacha Spelier 2,  Nadège Charlene Essonghe 3,  Virginie Poix 1,  Rebekah Kong 1,  Patrick Gizzi 4,  Claire Bourban 4,  Séverine Amand 5,  Christine Bailly 5,  Romain Guilbert 6,  David Hannebique 6,  Philippe Persoons 6,  Gwenaëlle Arhant 1,  Anne Prévotat 7,  Philippe Reix 8,  Dominique Hubert 9,  Michèle Gérardin 10,  Mathias Chamaillard 11,  Natalia Prevarskaya 3,  Sylvie Rebuffat 5,  George Shapovalov 3,  Jeffrey Beekman 2,  Fabrice Lejeune 12
Affiliations

Affiliations

  • 1 Univ. Lille, CNRS, Inserm, UMR9020-U1277 - CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000 Lille, France; Unité tumorigenèse et résistance aux traitements, Institut Pasteur de Lille, F-59000 Lille, France.
  • 2 Pediatric Respiratory Medicine, Wilhelmina Children's Hospital, University Medical Center, Utrecht University, 3584 EA Utrecht, The Netherlands; Regenerative Medicine Utrecht, University Medical Center, Utrecht University, 3584 CT Utrecht, The Netherlands; Centre for Living Technologies, University Medical Center, Utrecht University, 3584 CT Utrecht, The Netherlands.
  • 3 Univ. Lille, Inserm, U1003 - PHYCEL - Physiologie Cellulaire, F-59000 Lille, France; Laboratory of Excellence, Ion Channels Science and Therapeutics, 59655 Villeneuve d'Ascq, France.
  • 4 Plateforme de chimie biologique intégrative de Strasbourg, UAR 3286 CNRS - Université de Strasbourg, F-67404 Illkirch, France.
  • 5 Muséum national d'Histoire naturelle, Centre national de la Recherche scientifique, Laboratory Molecules of Communication and Adaptation of Microorganisms (MCAM), UMR 7245 CNRS-MNHN, CP 54, 57 rue Cuvier, 75005 Paris, France.
  • 6 Institut Pasteur de Lille - PLEHTA (Plateforme d'expérimentation et de Haute Technologie Animale), 59019 Lille, France.
  • 7 Univ. Lille, Clinique des Maladies Respiratoires, CRCM Hôpital Calmette, CHRU Lille, F-59000 Lille, France.
  • 8 CRCM pédiatrique Lyon. Hôpital Femme Mère Enfant. Hospices Civils de Lyon. UMR 5558 (EMET). CNRS, LBBE, Université de Lyon, F-69622 Villeurbanne, France.
  • 9 Pulmonary Department and Adult CF Centre, Cochin Hospital, AP-HP, Paris, France.
  • 10 CF pediatric centre, Robert Debré hospital, AP-HP, F-75019 Paris, France.
  • 11 Univ. Lille, Inserm, U1003 - PHYCEL - Physiologie Cellulaire, F-59000 Lille, France.
  • 12 Univ. Lille, CNRS, Inserm, UMR9020-U1277 - CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000 Lille, France; Unité tumorigenèse et résistance aux traitements, Institut Pasteur de Lille, F-59000 Lille, France. Electronic address: [email protected].
PMID: 36641622 DOI: 10.1016/j.ymthe.2023.01.014
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 new CF mouse model, in utero, and through breastfeeding, notably thanks 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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