{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T05:27:37Z","timestamp":1790832457261,"version":"4.1.0"},"reference-count":41,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2021,5,17]],"date-time":"2021-05-17T00:00:00Z","timestamp":1621209600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100008385","name":"Fondazione per la Ricerca sulla Fibrosi Cistica","doi-asserted-by":"publisher","award":["FFC9\/2019"],"award-info":[{"award-number":["FFC9\/2019"]}],"id":[{"id":"10.13039\/501100008385","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008385","name":"Fondazione per la Ricerca sulla Fibrosi Cistica","doi-asserted-by":"publisher","award":["FFC6\/2019"],"award-info":[{"award-number":["FFC6\/2019"]}],"id":[{"id":"10.13039\/501100008385","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008385","name":"Fondazione per la Ricerca sulla Fibrosi Cistica","doi-asserted-by":"publisher","award":["Task Force for Cystic Fibrosis"],"award-info":[{"award-number":["Task Force for Cystic Fibrosis"]}],"id":[{"id":"10.13039\/501100008385","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002426","name":"Fondazione Telethon","doi-asserted-by":"publisher","award":["TMLGCBX16TT"],"award-info":[{"award-number":["TMLGCBX16TT"]}],"id":[{"id":"10.13039\/501100002426","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Deletion of phenylalanine at position 508 (F508del) in the CFTR chloride channel is the most frequent mutation in cystic fibrosis (CF) patients. F508del impairs the stability and folding of the CFTR protein, thus resulting in mistrafficking and premature degradation. F508del-CFTR defects can be overcome with small molecules termed correctors. We investigated the efficacy and properties of VX-445, a newly developed corrector, which is one of the three active principles present in a drug (Trikafta\u00ae\/Kaftrio\u00ae) recently approved for the treatment of CF patients with F508del mutation. We found that VX-445, particularly in combination with type I (VX-809, VX-661) and type II (corr-4a) correctors, elicits a large rescue of F508del-CFTR function. In particular, in primary bronchial epithelial cells of CF patients, the maximal rescue obtained with corrector combinations including VX-445 was close to 60\u201370% of CFTR function in non-CF cells. Despite this high efficacy, analysis of ubiquitylation, resistance to thermoaggregation, protein half-life, and subcellular localization revealed that corrector combinations did not fully normalize F508del-CFTR behavior. Our study indicates that it is still possible to further improve mutant CFTR rescue with the development of corrector combinations having maximal effects on mutant CFTR structural and functional properties.<\/jats:p>","DOI":"10.3390\/ijms22105262","type":"journal-article","created":{"date-parts":[[2021,5,17]],"date-time":"2021-05-17T12:19:57Z","timestamp":1621253997000},"page":"5262","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":78,"title":["Partial Rescue of F508del-CFTR Stability and Trafficking Defects by Double Corrector Treatment"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9740-1171","authenticated-orcid":false,"given":"Valeria","family":"Capurro","sequence":"first","affiliation":[{"name":"U.O.C. Genetica Medica, IRCCS Istituto Giannina Gaslini, 16147 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeria","family":"Tomati","sequence":"additional","affiliation":[{"name":"U.O.C. Genetica Medica, IRCCS Istituto Giannina Gaslini, 16147 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elvira","family":"Sondo","sequence":"additional","affiliation":[{"name":"U.O.C. Genetica Medica, IRCCS Istituto Giannina Gaslini, 16147 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Renda","sequence":"additional","affiliation":[{"name":"Telethon Institute of Genetics and Medicine (TIGEM), 80078 Pozzuoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Borrelli","sequence":"additional","affiliation":[{"name":"Telethon Institute of Genetics and Medicine (TIGEM), 80078 Pozzuoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Pastorino","sequence":"additional","affiliation":[{"name":"U.O.C. Genetica Medica, IRCCS Istituto Giannina Gaslini, 16147 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Guidone","sequence":"additional","affiliation":[{"name":"Telethon Institute of Genetics and Medicine (TIGEM), 80078 Pozzuoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4265-1517","authenticated-orcid":false,"given":"Arianna","family":"Venturini","sequence":"additional","affiliation":[{"name":"Telethon Institute of Genetics and Medicine (TIGEM), 80078 Pozzuoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Giraudo","sequence":"additional","affiliation":[{"name":"D3-PharmaChemistry, Fondazione Istituto Italiano di Tecnologia, 16163 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sine","family":"Mandrup Bertozzi","sequence":"additional","affiliation":[{"name":"Analytical Chemistry Lab, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilaria","family":"Musante","sequence":"additional","affiliation":[{"name":"U.O.C. Genetica Medica, IRCCS Istituto Giannina Gaslini, 16147 Genova, Italy"},{"name":"Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa, 16132 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabio","family":"Bertozzi","sequence":"additional","affiliation":[{"name":"D3-PharmaChemistry, Fondazione Istituto Italiano di Tecnologia, 16163 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiziano","family":"Bandiera","sequence":"additional","affiliation":[{"name":"D3-PharmaChemistry, Fondazione Istituto Italiano di Tecnologia, 16163 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federico","family":"Zara","sequence":"additional","affiliation":[{"name":"U.O.C. Genetica Medica, IRCCS Istituto Giannina Gaslini, 16147 Genova, Italy"},{"name":"Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa, 16132 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis J. V.","family":"Galietta","sequence":"additional","affiliation":[{"name":"Telethon Institute of Genetics and Medicine (TIGEM), 80078 Pozzuoli, Italy"},{"name":"Department of Translational Medical Sciences (DISMET), University of Naples Federico II, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5161-1720","authenticated-orcid":false,"given":"Nicoletta","family":"Pedemonte","sequence":"additional","affiliation":[{"name":"U.O.C. Genetica Medica, IRCCS Istituto Giannina Gaslini, 16147 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,5,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2519","DOI":"10.1016\/S0140-6736(16)00576-6","article-title":"Cystic fibrosis","volume":"388","author":"Elborn","year":"2016","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1007\/s00018-016-2393-9","article-title":"Cystic fibrosis: A clinical view","volume":"74","author":"Castellani","year":"2017","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"113195","DOI":"10.1016\/j.ejmech.2021.113195","article-title":"Modulators of CFTR. Updates on clinical development and future directions","volume":"213","author":"Bardin","year":"2021","journal-title":"Eur. J. Med. 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