AUTHOR=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 

TITLE=Beyond Trikafta: new models to assess tissue dependent rescue of N1303K-CFTR

JOURNAL=Frontiers in Pharmacology

VOLUME=Volume 16 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2025.1661417

DOI=10.3389/fphar.2025.1661417

ISSN=1663-9812

ABSTRACT=RationaleRespiratory 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.MethodsTo 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.ResultsIn 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.ConclusionN1303K-CFTR shows tissue specific correction and suboptimal response to ETI which can be improved by API.