{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:06:52Z","timestamp":1792789612186,"version":"4.5.0"},"reference-count":31,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T00:00:00Z","timestamp":1791331200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T00:00:00Z","timestamp":1791331200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Russian Science Foundation","award":["22-15-00473-\u041f"],"award-info":[{"award-number":["22-15-00473-\u041f"]}],"id":[{"id":"https:\/\/ror.org\/03y2gwe85","id-type":"ROR","asserted-by":"crossref"}]},{"award":["22-15-00473-\u041f"],"award-info":[{"award-number":["22-15-00473-\u041f"]}],"id":[{"id":"https:\/\/ror.org\/03y2gwe85","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>The clinical response to elexacaftor\/tezacaftor\/ivacaftor (ETI) in people with cystic fibrosis carrying the rare cystic fibrosis transmembrane conductance regulator (CFTR) variant W1282R has not been well characterized. We retrospectively analyzed 12 people with cystic fibrosis treated with ETI for 3\u201336 months in addition to ongoing standard CF therapy. Baseline lung function was generally preserved in patients with available spirometry (median percent predicted forced expiratory volume in 1 s (ppFEV1), 110%; interquartile range (IQR), 93\u2013123), limiting the potential for further improvement in ppFEV1; no statistically significant change in ppFEV1 was detected during ETI therapy (p = 0.328). Paired data for ppFEV1, body mass index (BMI), and sweat conductivity were available for 8, 12, and 9 patients, respectively. CFTR function was assessed by intestinal current measurement (ICM; n = 4) and patient-derived intestinal organoids (n = 2). Functional testing demonstrated markedly reduced baseline CFTR activity. In the patient with paired ICM measurements before and during ETI therapy, restoration of CFTR-mediated chloride transport was observed, whereas ETI significantly increased forskolin-induced swelling (FIS) in both patient-derived organoid cultures (p &lt; 0.001 for each culture). BMI did not change significantly during ETI therapy (p = 0.269). Sweat conductivity showed a statistically significant overall reduction (median change, \u22123 mmol\/L; p = 0.031); however, marked reductions were observed in only two of nine patients. Interpretation is limited by the small retrospective cohort and incomplete availability of paired clinical and functional data. These findings indicate that functional responsiveness of W1282R-CFTR to ETI may not be accompanied by consistent improvement across the clinical outcomes assessed.<\/jats:p>","DOI":"10.3390\/ijms27198896","type":"journal-article","created":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T08:28:57Z","timestamp":1791361737000},"page":"8896","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["CFTR Functional Rescue and Heterogeneous Clinical Outcomes Following Elexacaftor\/Tezacaftor\/Ivacaftor Therapy in People with Cystic Fibrosis Carrying the W1282R Variant"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6395-0407","authenticated-orcid":false,"given":"Elena","family":"Kondratyeva","sequence":"first","affiliation":[{"name":"Research Centre for Medical Genetics,1 Moskvorechye St., 115552 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Efremova","sequence":"additional","affiliation":[{"name":"Research Centre for Medical Genetics,1 Moskvorechye St., 115552 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8814-5532","authenticated-orcid":false,"given":"Yuliya","family":"Melyanovskaya","sequence":"additional","affiliation":[{"name":"Research Centre for Medical Genetics,1 Moskvorechye St., 115552 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Zhekaite","sequence":"additional","affiliation":[{"name":"Research Centre for Medical Genetics,1 Moskvorechye St., 115552 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Sapelnikova","sequence":"additional","affiliation":[{"name":"Research Centre for Medical Genetics,1 Moskvorechye St., 115552 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Milovanov","sequence":"additional","affiliation":[{"name":"Research Centre for Medical Genetics,1 Moskvorechye St., 115552 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4905-1303","authenticated-orcid":false,"given":"Olga","family":"Shchagina","sequence":"additional","affiliation":[{"name":"Research Centre for Medical Genetics,1 Moskvorechye St., 115552 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Voronkova","sequence":"additional","affiliation":[{"name":"Research Centre for Medical Genetics,1 Moskvorechye St., 115552 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria","family":"Sherman","sequence":"additional","affiliation":[{"name":"Independent Researcher, Moscow 121108, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stanislav","family":"Krasovsky","sequence":"additional","affiliation":[{"name":"Research Centre for Medical Genetics,1 Moskvorechye St., 115552 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergey","family":"Kutsev","sequence":"additional","affiliation":[{"name":"Research Centre for Medical Genetics,1 Moskvorechye St., 115552 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dmitry","family":"Goldshtein","sequence":"additional","affiliation":[{"name":"Research Centre for Medical Genetics,1 Moskvorechye St., 115552 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,10,7]]},"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":"1809","DOI":"10.1056\/NEJMoa1908639","article-title":"Elexacaftor\u2013Tezacaftor\u2013Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele","volume":"381","author":"Middleton","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1940","DOI":"10.1016\/S0140-6736(19)32597-8","article-title":"Efficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: A double-blind, randomised, phase 3 trial","volume":"394","author":"Heijerman","year":"2019","journal-title":"Lancet"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1016\/j.jcf.2026.04.013","article-title":"ECFS statement on theratyping and theranostics in the context of rare and ultrarare CFTR variants in people with CF","volume":"25","author":"Burgel","year":"2026","journal-title":"J. Cyst. Fibros."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2300770","DOI":"10.1183\/13993003.00770-2023","article-title":"Organoid-guided synergistic treatment of minimal function CFTR mutations with CFTR modulators, roflumilast and simvastatin: A personalised approach","volume":"63","author":"Spelier","year":"2024","journal-title":"Eur. Respir. J."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1701","DOI":"10.1016\/j.celrep.2019.01.068","article-title":"Rectal organoids enable personalized treatment of cystic fibrosis","volume":"26","author":"Berkers","year":"2019","journal-title":"Cell Rep."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Pranke, I., Capurro, V., Chevalier, B., Pesce, E., Tomati, V., Pastorino, C., Kelly-Aubert, M., Hatton, A., Dreano, E., and Lena, M. (2025). Beyond Trikafta: New models to assess tissue dependent rescue of N1303K-CFTR. Front. Pharmacol., 16.","DOI":"10.3389\/fphar.2025.1661417"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1007\/BF00230224","article-title":"Two New Mutations Detected by Single-Strand Conformation Polymorphism Analysis in Cystic Fibrosis from Russia","volume":"91","author":"Ivaschenko","year":"1993","journal-title":"Hum. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"17640","DOI":"10.1038\/s41598-019-54158-2","article-title":"Nanomolar-potency \u2018co-potentiator\u2019 therapy for cystic fibrosis caused by a defined subset of minimal function CFTR mutants","volume":"9","author":"Phuan","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1016\/j.jcf.2024.02.006","article-title":"In vitro modulator responsiveness of 655 CFTR variants found in people with cystic fibrosis","volume":"23","author":"Bihler","year":"2024","journal-title":"J. Cyst. Fibros."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"83","DOI":"10.20953\/1817-7646-2022-3-83-91","article-title":"Selection of CFTR modulators for children with the W1282R variant","volume":"17","author":"Voronkova","year":"2022","journal-title":"Vopr. Prakt. Pediatr."},{"key":"ref_12","unstructured":"Amelina, E.L., Kashirskaya, N.Y., Kondratyeva, E.I., Krasovsky, S.A., Starinova, M.A., Voronkova, A.Y., and Ginter, E.K. (2025). Cystic Fibrosis Patient Registry of the Russian Federation: 2023, MEDPRACTIKA-M. (In Russian)."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Petrova, N.V., Kashirskaya, N.Y., Krasovskiy, S.A., Amelina, E.L., Kondratyeva, E.I., Marakhonov, A.V., Vasilyeva, T.A., Voronkova, A.Y., Sherman, V.D., and Ginter, E.K. (2020). Clinical Presentation of the c.3844T>C (p.Trp1282Arg, W1282R) Variant in Russian Cystic Fibrosis Patients. Genes, 11.","DOI":"10.3390\/genes11101137"},{"key":"ref_14","unstructured":"U.S. Food and Drug Administration (2026, September 23). TRIKAFTA (Elexacaftor, Tezacaftor, and Ivacaftor; Ivacaftor) Prescribing Information. Revised March 2026, Available online: https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2026\/212273s014lbl.pdf."},{"key":"ref_15","unstructured":"Melyanovskaya, Y.L. (2023). Molecular Epidemiology of Cystic Fibrosis in the Russian Federation and a Comprehensive Assessment of the Pathogenetic Role of CFTR Gene Variants Based on Studying the Function of Epithelial Ion Channels (ENaC, CFTR, CaCCs): Abstract of Candidate of Medical Sciences Thesis, Research Centre for Medical Genetics."},{"key":"ref_16","first-page":"162","article-title":"Determination of Reference Values for the Method of Intestinal Current Measurement in the Russian Federation","volume":"15","author":"Melyanovskaya","year":"2020","journal-title":"Med. News N. Cauc."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1007\/s12325-018-0860-4","article-title":"Efficacy and Safety of CFTR Corrector and Potentiator Combination Therapy in Patients with Cystic Fibrosis for the F508del-CFTR Homozygous Mutation: A Systematic Review and Meta-analysis","volume":"36","author":"Wu","year":"2019","journal-title":"Adv. Ther."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"614","DOI":"10.1016\/j.jcf.2019.10.022","article-title":"Forskolin-induced swelling of intestinal organoids correlates with disease severity in adults with cystic fibrosis and homozygous F508del mutations","volume":"19","author":"Berkers","year":"2020","journal-title":"J. Cyst. Fibros."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1902426","DOI":"10.1183\/13993003.02426-2019","article-title":"Correction of CFTR function in intestinal organoids to guide treatment of cystic fibrosis","volume":"57","author":"Ramalho","year":"2021","journal-title":"Eur. Respir. J."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Graeber, S.Y., Vitzthum, C., and Mall, M.A. (2021). Potential of Intestinal Current Measurement for Personalized Treatment of Patients with Cystic Fibrosis. J. Pers. Med., 11.","DOI":"10.3390\/jpm11050384"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"978","DOI":"10.1016\/S2213-2600(25)00190-0","article-title":"Sweat chloride and lung function responses to elexacaftor\u2013tezacaftor\u2013ivacaftor in people with cystic fibrosis with two versus one responsive CFTR variants: An analysis of two real-world observational studies","volume":"13","author":"Burgel","year":"2025","journal-title":"Lancet Respir. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"01308-2024","DOI":"10.1183\/23120541.01308-2024","article-title":"The response of rare CFTR mutations to specific modulator combinations","volume":"11","author":"Stanleigh","year":"2025","journal-title":"ERJ Open Res."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Kleinfelder, K., Lecca, P., Latorre, R.V., Mortali, C., Casati, S., Vanerio, S., Sorio, C., and Melotti, P. (2026). Drug Responsiveness in Patient-Derived Rectal Organoids Correlates with Clinical Response in CF Subjects: A Real-Life Analysis. Sci. Pharm., 94.","DOI":"10.3390\/scipharm94010013"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"00386-2024","DOI":"10.1183\/23120541.00386-2024","article-title":"Treatment effects of CFTR modulators on people with cystic fibrosis carrying the Q359K\/T360K variant","volume":"11","author":"Heching","year":"2025","journal-title":"ERJ Open Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"963","DOI":"10.1016\/j.jcf.2023.09.008","article-title":"Standards for the Care of People with Cystic Fibrosis (CF): A Timely and Accurate Diagnosis","volume":"22","author":"Castellani","year":"2023","journal-title":"J. Cyst. Fibros."},{"key":"ref_26","unstructured":"Ministry of Health of the Russian Federation (2025). Clinical Guidelines: Cystic Fibrosis (Mukoviscidoz), ID 372_3."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1016\/j.jcf.2022.01.004","article-title":"Standards of care guidance for sweat testing; phase two of the ECFS quality improvement programme","volume":"21","author":"Cirilli","year":"2022","journal-title":"J. Cyst. Fibros."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"594","DOI":"10.1136\/thx.2009.125088","article-title":"Intestinal current measurement for diagnostic classification of patients with questionable cystic fibrosis: Validation and reference data","volume":"65","author":"Derichs","year":"2010","journal-title":"Thorax"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"283","DOI":"10.18093\/0869-0189-2024-34-2-283-288","article-title":"Contribution of the intestinal current measurement method to assessment of the efficacy of CFTR modulators in cystic fibrosis","volume":"34","author":"Melyanovskaya","year":"2024","journal-title":"Pulmonologiya"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"100019","DOI":"10.1016\/j.xpro.2020.100019","article-title":"Protocol for Application, Standardization and Validation of the Forskolin-Induced Swelling Assay in Cystic Fibrosis Human Colon Organoids","volume":"1","author":"Vonk","year":"2020","journal-title":"STAR Protoc."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"145023","DOI":"10.1016\/j.gene.2020.145023","article-title":"Clinical and genetic characterization of patients with cystic fibrosis and functional assessment of the chloride channel with the pathogenic variant c.831G>A (p.Trp277*), described for the first time","volume":"761","author":"Kondratyeva","year":"2020","journal-title":"Gene"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/19\/8896\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T04:17:36Z","timestamp":1791519456000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/19\/8896"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,7]]},"references-count":31,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2026,10]]}},"alternative-id":["ijms27198896"],"URL":"https:\/\/doi.org\/10.3390\/ijms27198896","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,7]]}}}