N1303K-CFTR exhibits tissue-specific correction with a suboptimal response to ETI in sweat glands compared to airways, which can be further improved by apigenin.
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.
Pranke et al. (Wed,) studied this question.