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Here we developed intestinal organoids from subjects carrying S737F- and T465N-CFTR in trans with null alleles to evaluate their functional impact on CFTR protein function and their restoration upon CFTR modulator treatment. The characterization of S737F-CFTR was performed in two subjects recently assessed in nasal epithelial cells but not in colonoids.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Our functional analysis (Ussing chamber) confirmed that S737F-CFTR is a mild variant with residual function as investigated in colonoids of patients with S737F\/Dele22-24 and S737F\/W1282X genotypes. An increase of current upon Elexacaftor\/Tezacaftor\/Ivacaftor (ETI) treatment was recorded for the former genotype. T465N is a poorly characterized missense variant that strongly impacts CFTR function, as almost no CFTR-mediated anion secretion was registered for T465N\/Q39X colonoids. ETI treatment substantially improved CFTR-mediated anion secretion and increased the rescue of mature CFTR expression compared to either untreated colonoids or to dual CFTR modulator therapies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our study confirms the presence of a residual function of the S737F variant and its limited response to CFTR modulators while predicting for the first time the potential clinical benefit of Trikafta\u00ae for patients carrying the rare T465N variant.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13023-024-03334-3","type":"journal-article","created":{"date-parts":[[2024,9,13]],"date-time":"2024-09-13T09:03:24Z","timestamp":1726218204000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["CFTR modulators response of S737F and T465N CFTR variants on patient-derived rectal organoids"],"prefix":"10.1186","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1267-4814","authenticated-orcid":false,"given":"Karina","family":"Kleinfelder","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Melotti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anca Manuela","family":"Hristodor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Fevola","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni","family":"Taccetti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vito","family":"Terlizzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2739-4014","authenticated-orcid":false,"given":"Claudio","family":"Sorio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,9,13]]},"reference":[{"issue":"1","key":"3334_CR1","doi-asserted-by":"publisher","first-page":"86","DOI":"10.1038\/clpt.2012.183","volume":"93","author":"SS Antunovic","year":"2013","unstructured":"Antunovic SS, Lukac M, Vujovic D. 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Informed consent was obtained from all patients (or from their legal guardians) for the use of anonymous clinical data for research purposes.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Informed consent was obtained from all patients (or from their legal guardians) for the use of anonymous clinical data for research purposes.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"PM acted as paid expert testimony for Vertex Pharmaceuticals and declares no conflict of interest. The other authors declare no conflict of interest.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"343"}}