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

Jan 16, 2023

Experts: Catherine Leroy,Sacha Spelier,Nadège Charlene Essonghe,Virginie Poix,Rebekah Kong,Patrick Gizzi,Claire Bourban,Séverine Amand,Christine Bailly,Romain Guilbert,David Hannebique,Philippe Persoons,Gwenaëlle Arhant,Anne Prévotat,Philippe Reix,Dominique Hubert,Michèle Gérardin,Mathias Chamaillard,Natalia Prevarskaya,Sylvie Rebuffat,George Shapovalov,Jeffrey Beekman,Fabrice Lejeune

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.
Copyright © 2023. Published by Elsevier Inc.

Author

admin

View all posts

ABOUT THE EXPERTS

Catherine Leroy,Sacha Spelier,Nadège Charlene Essonghe,Virginie Poix,Rebekah Kong,Patrick Gizzi,Claire Bourban,Séverine Amand,Christine Bailly,Romain Guilbert,David Hannebique,Philippe Persoons,Gwenaëlle Arhant,Anne Prévotat,Philippe Reix,Dominique Hubert,Michèle Gérardin,Mathias Chamaillard,Natalia Prevarskaya,Sylvie Rebuffat,George Shapovalov,Jeffrey Beekman,Fabrice Lejeune

Catherine Leroy

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.

Sacha Spelier

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.

Nadège Charlene Essonghe

Univ. Lille, Inserm, U1003 – PHYCEL – Physiologie Cellulaire, F-59000 Lille, France; Laboratory of Excellence, Ion Channels Science and Therapeutics, 59655 Villeneuve d’Ascq, France.

Virginie Poix

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.

Rebekah Kong

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.

Patrick Gizzi

Plateforme de chimie biologique intégrative de Strasbourg, UAR 3286 CNRS – Université de Strasbourg, F-67404 Illkirch, France.

Claire Bourban

Plateforme de chimie biologique intégrative de Strasbourg, UAR 3286 CNRS – Université de Strasbourg, F-67404 Illkirch, France.

Séverine Amand

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.

Christine Bailly

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.

Romain Guilbert

Institut Pasteur de Lille – PLEHTA (Plateforme d’expérimentation et de Haute Technologie Animale), 59019 Lille, France.

David Hannebique

Institut Pasteur de Lille – PLEHTA (Plateforme d’expérimentation et de Haute Technologie Animale), 59019 Lille, France.

Philippe Persoons

Institut Pasteur de Lille – PLEHTA (Plateforme d’expérimentation et de Haute Technologie Animale), 59019 Lille, France.

Gwenaëlle Arhant

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.

Anne Prévotat

Univ. Lille, Clinique des Maladies Respiratoires, CRCM Hôpital Calmette, CHRU Lille, F-59000 Lille, France.

Philippe Reix

CRCM pédiatrique Lyon. Hôpital Femme Mère Enfant. Hospices Civils de Lyon. UMR 5558 (EMET). CNRS, LBBE, Université de Lyon, F-69622 Villeurbanne, France.

Dominique Hubert

Pulmonary Department and Adult CF Centre, Cochin Hospital, AP-HP, Paris, France.

Michèle Gérardin

CF pediatric centre, Robert Debré hospital, AP-HP, F-75019 Paris, France.

Mathias Chamaillard

Univ. Lille, Inserm, U1003 – PHYCEL – Physiologie Cellulaire, F-59000 Lille, France.

Natalia Prevarskaya

Univ. Lille, Inserm, U1003 – PHYCEL – Physiologie Cellulaire, F-59000 Lille, France; Laboratory of Excellence, Ion Channels Science and Therapeutics, 59655 Villeneuve d’Ascq, France.

Sylvie Rebuffat

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.

George Shapovalov

Univ. Lille, Inserm, U1003 – PHYCEL – Physiologie Cellulaire, F-59000 Lille, France; Laboratory of Excellence, Ion Channels Science and Therapeutics, 59655 Villeneuve d’Ascq, France.

Jeffrey Beekman

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.

Fabrice Lejeune

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: fabrice.lejeune@inserm.fr.