{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T14:08:20Z","timestamp":1782482900639,"version":"3.54.5"},"reference-count":37,"publisher":"European Respiratory Society (ERS)","issue":"5","license":[{"start":{"date-parts":[[2025,12,11]],"date-time":"2025-12-11T00:00:00Z","timestamp":1765411200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/publications.ersnet.org\/user-licence"}],"funder":[{"DOI":"10.13039\/501100003196","name":"Ministero della Salute","doi-asserted-by":"publisher","award":["PNRR-MR1-2023-12378412"],"award-info":[{"award-number":["PNRR-MR1-2023-12378412"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Fondazione Italiana per la Ricerca sulla Fibrosi Cistica","award":["FFC#9\/2022"],"award-info":[{"award-number":["FFC#9\/2022"]}]},{"name":"Fondazione Italiana per la Ricerca sulla Fibrosi Cistica","award":["GMRF#1\/2024"],"award-info":[{"award-number":["GMRF#1\/2024"]}]},{"DOI":"10.13039\/100000897","name":"Cystic Fibrosis Foundation","doi-asserted-by":"publisher","award":["GALIET22I0"],"award-info":[{"award-number":["GALIET22I0"]}],"id":[{"id":"10.13039\/100000897","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002426","name":"Fondazione Telethon","doi-asserted-by":"publisher","award":["TMLGMFU22TT, TMLGMFU23TT"],"award-info":[{"award-number":["TMLGMFU22TT, TMLGMFU23TT"]}],"id":[{"id":"10.13039\/501100002426","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["publications.ersnet.org"],"crossmark-restriction":true},"short-container-title":["Eur Respir J"],"accepted":{"date-parts":[[2025,11,21]]},"published-print":{"date-parts":[[2026,5]]},"abstract":"<jats:p>\n                    Loss of cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel function is the basic defect in cystic fibrosis (CF), a genetic disease that particularly affects the respiratory system, with bacterial infection and severe inflammation. People with CF carrying the most frequent mutation (F508del) or many types of missense mutations can be efficiently treated with drugs, named correctors and potentiators, that improve CFTR protein processing and channel activity. These treatments are ineffective on nonsense mutations that lead to nonsense-mediated RNA decay (NMD) and CFTR protein truncation. We tested the efficacy of a triple combination of small molecules including the readthrough agent ELX-02, the CFTR corrector VX-809, and the eRF3A degrader CC-90009, on cultured airway epithelia from patients carrying the G542X mutation. The treatment resulted in a significant but relatively modest (three-fold) increase in CFTR function. Importantly, the efficacy of the triple drug combination was greatly amplified under inflammatory conditions,\n                    <jats:italic>i.e.<\/jats:italic>\n                    by exposing the epithelia to interleukin (IL)-4 (15-fold increase) or to IL-17A\/tumour necrosis factor-\u03b1 (nine-fold increase). Similar effects were also found in epithelia with the W1282X mutation. The large rescue of CFTR function under inflammatory conditions was paralleled by the appearance of full-length CFTR protein and by the increase in CFTR mRNA. The effect of inflammatory stimuli could be mediated by enhanced translational readthrough and\/or reduced NMD. Our results suggest that rescue of CFTR with nonsense mutations could be more effective than expected\n                    <jats:italic>in vivo<\/jats:italic>\n                    . Our findings may also lead to the identification of novel targets to correct the effect of nonsense mutations in CF and other genetic diseases.\n                  <\/jats:p>","DOI":"10.1183\/13993003.01171-2025","type":"journal-article","created":{"date-parts":[[2025,12,11]],"date-time":"2025-12-11T18:35:25Z","timestamp":1765478125000},"page":"2501171","update-policy":"https:\/\/doi.org\/10.1183\/ers-crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Rescue of the CFTR chloride channel with nonsense mutations is markedly improved under inflammatory conditions"],"prefix":"10.1183","volume":"67","author":[{"given":"Anna","family":"Borrelli","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arianna","family":"Venturini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Guidone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"De Santis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enza","family":"Montemitro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federico","family":"Alghisi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabiana","family":"Ciciriello","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis J.V.","family":"Galietta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"81","published-online":{"date-parts":[[2025,12,11]]},"reference":[{"key":"2026050703100770000_67.5.2501171.1","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1038\/s41572-024-00538-6","article-title":"Cystic fibrosis","volume":"10","author":"Mall","year":"2024","journal-title":"Nat Rev Dis Primers"},{"key":"2026050703100770000_67.5.2501171.2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)32542-3"},{"key":"2026050703100770000_67.5.2501171.3","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81724-9"},{"key":"2026050703100770000_67.5.2501171.4","doi-asserted-by":"publisher","DOI":"10.1038\/nature11130"},{"key":"2026050703100770000_67.5.2501171.5","unstructured":"Cystic Fibrosis Mutation Database. Date last updated: 25 April 2011. www.genet.sickkids.on.ca\/StatisticsPage.html"},{"key":"2026050703100770000_67.5.2501171.6","unstructured":"US CF Foundation , Johns Hopkins University , The Hospital for Sick Children . CFTR2 Variant List History. Date last updated: 25 September 2024. https:\/\/cftr2.org\/mutations_history"},{"key":"2026050703100770000_67.5.2501171.7","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.E14-04-0935"},{"key":"2026050703100770000_67.5.2501171.8","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0904709106"},{"key":"2026050703100770000_67.5.2501171.9","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1105787108"},{"key":"2026050703100770000_67.5.2501171.10","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2011.11.023"},{"key":"2026050703100770000_67.5.2501171.11","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2011.11.024"},{"key":"2026050703100770000_67.5.2501171.12","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa1807120"},{"key":"2026050703100770000_67.5.2501171.13","doi-asserted-by":"crossref","first-page":"e139983","DOI":"10.1172\/jci.insight.139983","article-title":"Allosteric folding correction of F508del and rare CFTR mutants by elexacaftor-tezacaftor-ivacaftor (Trikafta) combination","volume":"5","author":"Veit","year":"2020","journal-title":"JCI Insight"},{"key":"2026050703100770000_67.5.2501171.14","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcf.2011.12.005"},{"key":"2026050703100770000_67.5.2501171.15","doi-asserted-by":"crossref","first-page":"2793","DOI":"10.3390\/cells10102793","article-title":"Therapeutic approaches for patients with cystic fibrosis not eligible for current CFTR modulators","volume":"10","author":"Fajac","year":"2021","journal-title":"Cells"},{"key":"2026050703100770000_67.5.2501171.16","first-page":"326","article-title":"The effect of premature termination codon mutations on CFTR mRNA abundance in human nasal epithelium and intestinal organoids: a basis for read-through therapies in cystic fibrosis","volume":"40","author":"Clarke","year":"2019","journal-title":"Hum Mutat"},{"key":"2026050703100770000_67.5.2501171.17","doi-asserted-by":"crossref","first-page":"141","DOI":"10.3390\/biomedicines10010141","article-title":"Nonsense-mediated mRNA decay, a finely regulated mechanism","volume":"10","author":"Lejeune","year":"2022","journal-title":"Biomedicines"},{"key":"2026050703100770000_67.5.2501171.18","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2023.01.004"},{"key":"2026050703100770000_67.5.2501171.19","doi-asserted-by":"publisher","DOI":"10.1038\/nm1197-1280"},{"key":"2026050703100770000_67.5.2501171.20","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2013-0282OC"},{"key":"2026050703100770000_67.5.2501171.21","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.120.265595"},{"key":"2026050703100770000_67.5.2501171.22","doi-asserted-by":"crossref","first-page":"1347","DOI":"10.1080\/13543784.2020.1828862","article-title":"ELX-02: an investigational read-through agent for the treatment of nonsense mutation-related genetic disease","volume":"29","author":"Kerem","year":"2020","journal-title":"Expert Opin Investig Drugs"},{"key":"2026050703100770000_67.5.2501171.23","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkab194"},{"key":"2026050703100770000_67.5.2501171.24","doi-asserted-by":"publisher","DOI":"10.1172\/JCI154571"},{"key":"2026050703100770000_67.5.2501171.25","doi-asserted-by":"crossref","first-page":"e150398","DOI":"10.1172\/JCI150398","article-title":"Inflammatory cytokines TNF-\u03b1 and IL-17 enhance the efficacy of cystic fibrosis transmembrane conductance regulator modulators","volume":"131","author":"Rehman","year":"2021","journal-title":"J Clin Invest"},{"key":"2026050703100770000_67.5.2501171.26","doi-asserted-by":"crossref","first-page":"628722","DOI":"10.3389\/fphar.2021.628722","article-title":"Airway epithelial inflammation in vitro augments the rescue of mutant CFTR by current CFTR modulator therapies","volume":"12","author":"Gentzsch","year":"2021","journal-title":"Front Pharmacol"},{"key":"2026050703100770000_67.5.2501171.27","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2012.240838"},{"key":"2026050703100770000_67.5.2501171.28","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2016.05.012"},{"key":"2026050703100770000_67.5.2501171.29","doi-asserted-by":"crossref","first-page":"2619","DOI":"10.1113\/JP287891","article-title":"The apical mucus layer alters the pharmacological properties of the airway epithelium","volume":"603","author":"Guidone","year":"2025","journal-title":"J Physiol"},{"key":"2026050703100770000_67.5.2501171.30","doi-asserted-by":"crossref","first-page":"e164944","DOI":"10.1172\/jci.insight.164944","article-title":"Airway surface hyperviscosity and defective mucociliary transport by IL-17\/TNF-\u03b1 are corrected by \u03b2-adrenergic stimulus","volume":"7","author":"Guidone","year":"2022","journal-title":"JCI Insight"},{"key":"2026050703100770000_67.5.2501171.31","doi-asserted-by":"crossref","first-page":"11972","DOI":"10.3390\/ijms222111972","article-title":"Comprehensive analysis of combinatorial pharmacological treatments to correct nonsense mutations in the CFTR gene","volume":"22","author":"Venturini","year":"2021","journal-title":"Int J Mol Sci"},{"key":"2026050703100770000_67.5.2501171.32","doi-asserted-by":"publisher","DOI":"10.1038\/srep36016"},{"key":"2026050703100770000_67.5.2501171.33","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.00716-2019"},{"key":"2026050703100770000_67.5.2501171.34","doi-asserted-by":"crossref","first-page":"2344","DOI":"10.1038\/s41467-022-29935-9","article-title":"CFTR mRNAs with nonsense codons are degraded by the SMG6-mediated endonucleolytic decay pathway","volume":"13","author":"Sanderlin","year":"2022","journal-title":"Nat Commun"},{"key":"2026050703100770000_67.5.2501171.35","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21249449"},{"key":"2026050703100770000_67.5.2501171.36","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2023.113056"},{"key":"2026050703100770000_67.5.2501171.37","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2018.08.022"}],"container-title":["European Respiratory Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1183\/13993003.01171-2025","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T10:10:22Z","timestamp":1778148622000},"score":1,"resource":{"primary":{"URL":"https:\/\/publications.ersnet.org\/lookup\/doi\/10.1183\/13993003.01171-2025"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,11]]},"references-count":37,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2026,5,7]]},"published-print":{"date-parts":[[2026,5]]}},"alternative-id":["10.1183\/13993003.01171-2025"],"URL":"https:\/\/doi.org\/10.1183\/13993003.01171-2025","relation":{},"ISSN":["0903-1936","1399-3003"],"issn-type":[{"value":"0903-1936","type":"print"},{"value":"1399-3003","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,11]]}}}