Iwona Pranke, Valeria Capurro, B. Chevalier, Emanuela Pesce, Valeria Tomati, Cristina Pastorino, Mairead Kelly, Aurélie Hatton, Elise Dréano, Mariateresa Lena, Renata Bocciardi, Federico Zara, Stefano Pantano, Vito Terlizzi, Cristina Lucanto, Stefano Costa, Laura Claut, Valeria Daccò, Piercarlo Poli, Massimo Maschio, Benedetta Fabrizzi, N. Caporelli, Marco Cipolli, Sonia Volpi, F. Chedevergne, Laure Cosson, Julie Macey, Sophie Ramel, Laurence Weiss, Dominique Grenet, Laurence Le Clainche-Viala, Benoît Douvry, Bruno Ravoninjatovo, Camille Audousset, Aurélie Tatopoulos, Bénédicte Richaud-Thiriez, Melissa Baravalle, Guillaume Thouvenin, Guillaume Labbé, Marie Mittaine, Philippe Reix, I. Durieu, Julie Mankikian, S. Bui, Thao Nguyen‐Khoa, Karim Khoukh, Clémence Martin, Jennifer Da Silva, P. De Carli, Carlo Castellani, Federico Cresta, Luis J. V. Galietta, Anne Guillemaut, Emmanuelle Girodon, Natacha Rémus, M. Bulcaen, M. Ensinck, Mirosław Zając, Marianne Carlon, Jean Lebihan, Pierre‐Régis Burgel, Isabelle Sermet‐Gaudelus, Alexandre Hinzpeter, Nicoletta Pedemonte
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 (HCO 3 -) 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.