Cystic fibrosis airway inflammation enables elexacaftor/tezacaftor/ivacaftor-mediated rescue of N1303K<i>CFTR</i>mutation
Martina Gentzsch, Brooke Baker, Deborah M. Cholon, Charissa W. Kam, Cameron J. McKinzie, Katherine A. Despotes, Susan E. Boyles, Nancy L. Quinney, Charles R. Esther, Carla M. P. Ribeiro
Abstract
Cystic fibrosis transmembrane conductance regulator (CFTR) modulators promote robust clinical improvements in people with cystic fibrosis (pwCF) with qualifying genotypes [1, 2]. A triple combination therapy consisting of two CFTR folding correctors (elexacaftor and tezacaftor) plus CFTR potentiator ivacaftor, referred to as ETI, has been approved by the FDA and European agencies (<https://www.fda.gov/news-events/press-announcements/fda-approves-new-breakthrough-therapy-cystic-fibrosis>, <https://www.ema.europa.eu/en/medicines/human/EPAR/kaftrio>; <https://ec.europa.eu/health/documents/community-register/html/h1468.htm>) as highly effective modulatory therapy (HEMT) that improves lung function, decreases pulmonary exacerbation rates, increases body mass index (BMI), and lowers sweat chloride concentrations in pwCF with at least one copy of F508del CFTR mutation [1–3]. However, ∼10% of pwCF do not have the F508del mutation or other genotypes that are currently approved for HEMT. Footnotes This manuscript has recently been accepted for publication in the ERJ Open Research . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJOR online. Please open or download the PDF to view this article. Conflict of interest: M. Gentzsch directs the CFTR Functional Analysis Core of the CF Foundation Research Development Program BOUCHE19R0 and the CF Molecular/Functional Measurement Core of the NIH CFRTCC Program P30DK065988. M. Gentzsch and C.M.P. Ribeiro are recipients of a Boost Award from the School of Medicine at the University of North Carolina and have obtained support for registration (NACFC) or travel (ECFS Conference) to conferences. Conflict of interest: C.W. Kam reports grants from the CFF, Friends Fighting Cystic Fibrosis, and the American Society of Health-System Pharmacists Foundation. Conflict of interest: C.J. McKinzie received funding from the CFF and consulting fees from Vertex Pharmaceuticals, Inc. Conflict of interest: K.A. Despotes received funding from the CFF. C.R. Esther directs a National Resource Center Core that is funded by the CFF and obtained consulting fees from the CFF. Conflict of interest: B. Baker, D.M. Cholon, S.E. Boyles, and N.L. Quinney report no conflict of interest.