{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T21:17:17Z","timestamp":1791839837480,"version":"4.3.4"},"reference-count":29,"publisher":"Public Library of Science (PLoS)","issue":"2","license":[{"start":{"date-parts":[[2025,2,14]],"date-time":"2025-02-14T00:00:00Z","timestamp":1739491200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100019408","name":"Marcus Foundation","doi-asserted-by":"publisher","award":["Project #00117885"],"award-info":[{"award-number":["Project #00117885"]}],"id":[{"id":"10.13039\/100019408","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Background<\/jats:title>\n<jats:p>Non-cystic fibrosis bronchiectasis (NCFBE) is a disease that exhibits dilatation of airways, airflow obstruction, persistent cough, excessive sputum production, and refractory respiratory infections. NCFBE exhibits clinical and pathological manifestations similar to key features of cystic fibrosis (CF) lung disease. In CF, pathogenesis results from dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR), and diagnosis is made by demonstrating elevated sweat chloride concentrations (typically \u226560 mEq\/L), two CFTR mutations known to be causal, multi-organ tissue injury, or combination(s) of these findings.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Objective<\/jats:title>\n<jats:p>Based on a considerable body of evidence, we believe many patients with NCFBE have disease likely to benefit from drugs such as elexacaftor\/tezacaftor\/ivacaftor (ETI) that activate CFTR-dependent ion transport. ETI is currently prescribed solely for treatment of CF and has not been adequately tested or proposed for patients with NCFBE, many of whom exhibit decreased CFTR function. Accordingly, we are conducting a clinical trial of ETI in subjects carrying a diagnosis of NCFBE.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Methods<\/jats:title>\n<jats:p>Participants will exhibit one disease-causing CFTR mutation and\/or sweat chloride measurements of 30\u201359 mEq\/L. Cutaneous punch biopsy or blood samples will be obtained for iPS cell differentiation into airway epithelial monolayers\u2013which will then be tested for response to ETI. Each patient will be given CFTR modulator treatment for approximately four weeks, with monitoring of clinical endpoints that include FEV<jats:sub>1<\/jats:sub> (forced expiratory volume in one second), sweat chloride, quality of life questionnaire, and weight. The study will evaluate response of patients with NCFBE to ETI, and test usefulness of iPSC-derived airway epithelial monolayers as a novel in vitro technology for predicting clinical benefit.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Trial registration<\/jats:title>\n<jats:p>This trial is registered at clinicaltrials.gov (Identifier: <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/clinicaltrials.gov\/ct2\/show\/NCT05743946\" xlink:type=\"simple\">NCT05743946<\/jats:ext-link>. Date: 02\/23\/2023).<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0316721","type":"journal-article","created":{"date-parts":[[2025,2,14]],"date-time":"2025-02-14T18:26:44Z","timestamp":1739557604000},"page":"e0316721","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":6,"title":["Evaluating elexacaftor\/tezacaftor\/ivacaftor (ETI; Trikafta\u2122) for treatment of patients with non-cystic fibrosis bronchiectasis (NCFBE): A clinical study protocol"],"prefix":"10.1371","volume":"20","author":[{"given":"Colin E.","family":"Swenson","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William R.","family":"Hunt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Candela","family":"Manfredi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana J.","family":"Beltran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeong S.","family":"Hong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian R.","family":"Davis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shingo","family":"Suzuki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Barill\u00e1","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andras","family":"Rab","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cynthia","family":"Chico","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joy","family":"Dangerfield","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashleigh","family":"Streby","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erin","family":"Barton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth M.","family":"Cox","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arlene A.","family":"Stecenko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrianna","family":"Westbrook","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Kapolka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9341-3354","authenticated-orcid":true,"given":"Eric J.","family":"Sorscher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,2,14]]},"reference":[{"issue":"10150","key":"pone.0316721.ref001","doi-asserted-by":"crossref","first-page":"880","DOI":"10.1016\/S0140-6736(18)31767-7","article-title":"Advances in bronchiectasis: endotyping, genetics, microbiome, and disease heterogeneity.","volume":"392","author":"PA Flume","year":"2018","journal-title":"Lancet."},{"issue":"1","key":"pone.0316721.ref002","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1038\/s41572-018-0042-3","article-title":"Bronchiectasis.","volume":"4","author":"JD Chalmers","year":"2018","journal-title":"Nat Rev Dis Primers"},{"issue":"2","key":"pone.0316721.ref003","doi-asserted-by":"crossref","DOI":"10.1111\/ijcp.12924","article-title":"Suspecting non-cystic fibrosis bronchiectasis: What the busy primary care clinician needs to know.","volume":"71","author":"DJ Maselli","year":"2017","journal-title":"Int J Clin Pract."},{"issue":"6450","key":"pone.0316721.ref004","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1126\/science.aaw0553","article-title":"Making precision medicine personal for cystic fibrosis","volume":"365","author":"C Manfredi","year":"2019","journal-title":"Science"},{"key":"pone.0316721.ref005","doi-asserted-by":"crossref","first-page":"1438","DOI":"10.3389\/fimmu.2020.01438","article-title":"Role of Cystic Fibrosis Bronchial Epithelium in Neutrophil Chemotaxis.","volume":"11","author":"G Cabrini","year":"2020","journal-title":"Front Immunol."},{"key":"pone.0316721.ref006","volume-title":"Harrison\u2019s Principles of Internal Medicine","author":"EJ Sorscher","year":"2022","edition":"21"},{"issue":"1","key":"pone.0316721.ref007","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1513\/AnnalsATS.201805-325RL","article-title":"Acquired cystic fibrosis transmembrane conductance regulator dysfunction and radiographic bronchiectasis in current and former smokers: A cross-sectional study.","volume":"16","author":"K Teerapuncharoen","year":"2019","journal-title":"Ann Am Thorac Soc"},{"issue":"3","key":"pone.0316721.ref008","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/j.wjorl.2018.09.001","article-title":"Acquired cystic fibrosis transmembrane conductance regulator dysfunction.","volume":"4","author":"C Banks","year":"2018","journal-title":"World J Otorhinolaryngol Head Neck Surg"},{"issue":"4","key":"pone.0316721.ref009","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1093\/hmg\/4.4.635","article-title":"Increased incidence of cystic fibrosis gene mutations in adults with disseminated bronchiectasis","volume":"4","author":"PF Pignatti","year":"1995","journal-title":"Hum Mol Genet"},{"issue":"6","key":"pone.0316721.ref010","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1111\/j.0009-9163.2004.00265.x","article-title":"Bronchiectasis in adult patients: an expression of heterozygosity for CFTR gene mutations?","volume":"65","author":"T Casals","year":"2004","journal-title":"Clin Genet"},{"issue":"3","key":"pone.0316721.ref011","doi-asserted-by":"crossref","first-page":"1621","DOI":"10.1073\/pnas.1914912117","article-title":"Cystic fibrosis carriers are at increased risk for a wide range of cystic fibrosis-related conditions","volume":"117","author":"AC Miller","year":"2020","journal-title":"Proc Natl Acad Sci U S A"},{"key":"pone.0316721.ref012","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1146\/annurev-med-042120-020148","article-title":"Clinical Phenotypes of Cystic Fibrosis Carriers.","volume":"73","author":"PM Polgreen","year":"2022","journal-title":"Annu Rev Med."},{"issue":"10","key":"pone.0316721.ref013","doi-asserted-by":"crossref","first-page":"1078","DOI":"10.1164\/rccm.200909-1434OC","article-title":"Cystic fibrosis transmembrane conductance regulator channel dysfunction in non-cystic fibrosis bronchiectasis","volume":"181","author":"T Bienvenu","year":"2010","journal-title":"Am J Respir Crit Care Med"},{"issue":"4","key":"pone.0316721.ref014","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1177\/1479972317709649","article-title":"Prevalence and incidence of noncystic fibrosis bronchiectasis among US adults in 2013.","volume":"14","author":"D Weycker","year":"2017","journal-title":"Chron Respir Dis"},{"issue":"19","key":"pone.0316721.ref015","doi-asserted-by":"crossref","first-page":"1809","DOI":"10.1056\/NEJMoa1908639","article-title":"Elexacaftor-Tezacaftor-Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele","volume":"381","author":"PG Middleton","year":"2019","journal-title":"N Engl J Med"},{"issue":"23","key":"pone.0316721.ref016","first-page":"2208","article-title":"Triple Therapy for Cystic Fibrosis Phe508del-Gating and -Residual Function Genotypes. Reply","volume":"385","author":"PJ Barry","year":"2021","journal-title":"N Engl J Med"},{"issue":"4","key":"pone.0316721.ref017","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1097\/FJC.0b013e318247f642","article-title":"Induced pluripotent stem cells as a disease modeling and drug screening platform","volume":"60","author":"AD Ebert","year":"2012","journal-title":"J Cardiovasc Pharmacol"},{"key":"pone.0316721.ref018","doi-asserted-by":"crossref","first-page":"1662","DOI":"10.3389\/fphar.2019.01662","article-title":"CFTR Modulators: The Changing Face of Cystic Fibrosis in the Era of Precision Medicine.","volume":"10","author":"M. Lopes-Pacheco","year":"2019","journal-title":"Front Pharmacol."},{"issue":"4","key":"pone.0316721.ref019","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1016\/j.stemcr.2015.02.005","article-title":"Targeted correction and restored function of the CFTR gene in cystic fibrosis induced pluripotent stem cells","volume":"4","author":"AM Crane","year":"2015","journal-title":"Stem Cell Reports"},{"issue":"6","key":"pone.0316721.ref020","doi-asserted-by":"crossref","first-page":"2277","DOI":"10.1172\/JCI89950","article-title":"Prospective isolation of NKX2-1-expressing human lung progenitors derived from pluripotent stem cells","volume":"127","author":"F Hawkins","year":"2017","journal-title":"J Clin Invest"},{"issue":"4","key":"pone.0316721.ref021","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1016\/j.stem.2017.08.014","article-title":"Differentiation of Human Pluripotent Stem Cells into Functional Lung Alveolar Epithelial Cells.","volume":"21","author":"A Jacob","year":"2017","journal-title":"Cell Stem Cell"},{"issue":"7","key":"pone.0316721.ref022","doi-asserted-by":"crossref","first-page":"1684","DOI":"10.1016\/j.ymthe.2020.04.021","article-title":"Highly efficient gene editing of cystic fibrosis patient-derived airway basal cells results in functional CFTR correction","volume":"28","author":"S Suzuki","year":"2020","journal-title":"Mol Ther"},{"key":"pone.0316721.ref023","doi-asserted-by":"crossref","first-page":"S316","DOI":"10.1016\/S1569-1993(21)02090-7","article-title":"667: Development of an iPSC-based airway epithelial platform for evaluating patient-specific responses to modulators","volume":"20","author":"C Barill\u00e0","year":"2021","journal-title":"Journal of Cystic Fibrosis"},{"key":"pone.0316721.ref024","doi-asserted-by":"crossref","first-page":"S271","DOI":"10.1016\/S1569-1993(21)01995-0","article-title":"572: Clinical and iPSC-derived airway epithelial responses to elexacaftor\/tezacaftor\/ivacaftor in CF patients without an approved modulator","volume":"20","author":"R Linnemann","year":"2021","journal-title":"Journal of Cystic Fibrosis"},{"key":"pone.0316721.ref025","doi-asserted-by":"crossref","first-page":"S303","DOI":"10.1016\/S1569-1993(21)02061-0","article-title":"638: Demonstration of pharmacologic N1303 K CFTR rescue in heterologous and human tissue-based model systems","volume":"20","author":"J Brewington","year":"2021","journal-title":"Journal of Cystic Fibrosis"},{"issue":"Suppl 40","key":"pone.0316721.ref026","first-page":"S14","article-title":"Personalized medicine for cystic fibrosis: establishing human model systems.","volume":"50","author":"H Mou","year":"2015","journal-title":"Pediatr Pulmonol"},{"key":"pone.0316721.ref027","first-page":"28","article-title":"Confidence curves and improved exact confidence intervals for discrete distributions","author":"H. Blaker","year":"2000","journal-title":"Canadian Journal of Statistics"},{"issue":"7","key":"pone.0316721.ref028","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1016\/S2213-2600(14)70132-8","article-title":"A CFTR corrector (lumacaftor) and a CFTR potentiator (ivacaftor) for treatment of patients with cystic fibrosis who have a phe508del CFTR mutation: a phase 2 randomised controlled trial.","volume":"2","author":"MP Boyle","year":"2014","journal-title":"Lancet Respir Med"},{"issue":"1","key":"pone.0316721.ref029","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.jcf.2016.11.008","article-title":"Biological variability of the sweat chloride in diagnostic sweat tests: A retrospective analysis.","volume":"16","author":"F Vermeulen","year":"2017","journal-title":"J Cyst Fibros"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0316721","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,14]],"date-time":"2025-02-14T18:26:59Z","timestamp":1739557619000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0316721"}},"subtitle":[],"editor":[{"given":"Johanna","family":"Pruller","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2025,2,14]]},"references-count":29,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2025,2,14]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0316721","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,14]]}}}