Rationale: Respiratory status of people with Cystic Fibrosis (pwCF) carrying N1303K is improved by Elexacaftor/Tezacaftor/Ivacaftor (ETI) but, contrary to other mutations, the impact on sweat test results is limited. Methods: To explore this discrepancy, we implemented new sweat gland and respiratory cell lines stably expressing Wild type (WT)-, F508del- and N1303K-CFTR. CFTR dependent chloride (Cl-) and bicarbonate (HCO3-) transport was measured by short circuit current in these new models and in primary Human Nasal Epithelial Cells (HNECs). CFTR expression was evaluated by Western blot. Results: In the airway and the sweat gland cells expressing F508del-CFTR, ETI induced maturation of CFTR and increased Cl- transport. In the respiratory cell lines and HNECs, N1303K-CFTR generated both immature and mature forms of CFTR. Correction by ETI increased CFTR amounts without promoting its maturation and improved Cl- secretion. N1303K-CFTR channel activity was markedly increased by co-potentiation of IVA with Apigenin. In the sweat gland, N1303K-CFTR was expressed as a globally misfolded protein, non-rescuable by ETI. API treatment to 2 patients improved FEV1 without lowering sweat Cl- content. Conclusion: N1303K-CFTR shows tissue specific correction and suboptimal response to ETI which can be improved by API.
Beyond Trikafta: new models to assess tissue dependent rescue of N1303K-CFTR / Pranke, Iwona; Capurro, Valeria; Chevalier, Benoit; Pesce, Emanuela; Tomati, Valeria; Pastorino, Cristina; Kelly-Aubert, Mairead; Hatton, Aurelie; Dreano, Elise; Lena, Mariateresa; Bocciardi, Renata; Zara, Federico; Pantano, Stefano; Terlizzi, Vito; Lucanto, Cristina; Costa, Stefano; Claut, Laura; Daccò, Valeria; Poli, Piercarlo; Maschio, Massimo; Fabrizzi, Benedetta; Caporelli, Nicole; Cipolli, Marco; Volpi, Sonia; Chedevergne, Frederique; Cosson, Laure; Macey, Julie; Ramel, Sophie; Weiss, Laurence; Grenet, Dominique; Le Clainche-Viala, Laurence; Douvry, Benoit; Ravoninjatovo, Bruno; Audousset, Camille; Tatopoulos, Aurélie; Richaud-Thiriez, Bénédicte; Baravalle, Melissa; Thouvenin, Guillaume; Labbé, Guillaume; Mittaine, Marie; Reix, Philippe; Durieu, Isabelle; Mankikian, Julie; Bui, Stéphanie; Nguyen-Khoa, Thao; Khoukh, Karim; Martin, Clémence; Da Silva, Jennifer; De Carli, Paola; Castellani, Carlo; Cresta, Federico; Galietta, Luis; Guillemaut, Anne; Girodon, Emmanuelle; Remus, Natacha; Bulcaen, Mathis; Ensinck, Marjolein; Zajac, Miroslaw; Carlon, Marianne; Lebihan, Jean; Burgel, Pierre-Régis; Sermet-Gaudelus, Isabelle; Hinzpeter, Alexandre; Pedemonte, Nicoletta. - In: FRONTIERS IN PHARMACOLOGY. - ISSN 1663-9812. - 16:(2025). [10.3389/fphar.2025.1661417]
Beyond Trikafta: new models to assess tissue dependent rescue of N1303K-CFTR
Galietta, Luis;
2025
Abstract
Rationale: Respiratory status of people with Cystic Fibrosis (pwCF) carrying N1303K is improved by Elexacaftor/Tezacaftor/Ivacaftor (ETI) but, contrary to other mutations, the impact on sweat test results is limited. Methods: To explore this discrepancy, we implemented new sweat gland and respiratory cell lines stably expressing Wild type (WT)-, F508del- and N1303K-CFTR. CFTR dependent chloride (Cl-) and bicarbonate (HCO3-) transport was measured by short circuit current in these new models and in primary Human Nasal Epithelial Cells (HNECs). CFTR expression was evaluated by Western blot. Results: In the airway and the sweat gland cells expressing F508del-CFTR, ETI induced maturation of CFTR and increased Cl- transport. In the respiratory cell lines and HNECs, N1303K-CFTR generated both immature and mature forms of CFTR. Correction by ETI increased CFTR amounts without promoting its maturation and improved Cl- secretion. N1303K-CFTR channel activity was markedly increased by co-potentiation of IVA with Apigenin. In the sweat gland, N1303K-CFTR was expressed as a globally misfolded protein, non-rescuable by ETI. API treatment to 2 patients improved FEV1 without lowering sweat Cl- content. Conclusion: N1303K-CFTR shows tissue specific correction and suboptimal response to ETI which can be improved by API.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
