{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T16:30:37Z","timestamp":1787502637938,"version":"build-2736575974"},"reference-count":54,"publisher":"European Respiratory Society (ERS)","issue":"1","license":[{"start":{"date-parts":[[2024,8,22]],"date-time":"2024-08-22T00:00:00Z","timestamp":1724284800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Wellcome Trust\/Department of Health","award":["Health Innovation Challenge Fund"],"award-info":[{"award-number":["Health Innovation Challenge Fund"]}]},{"name":"Medicor Foundation"},{"DOI":"10.13039\/100001003","name":"Boehringer Ingelheim","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001003","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["publications.ersnet.org"],"crossmark-restriction":true},"short-container-title":["Eur Respir J"],"accepted":{"date-parts":[[2024,8,2]]},"published-print":{"date-parts":[[2025,1]]},"abstract":"<jats:sec>\n                    <jats:title>Rationale and objective<\/jats:title>\n                    <jats:p>Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. CFTR modulators offer significant improvements, but \u223c10% of patients remain nonresponsive or are intolerant. This study provides an analysis of rSIV.F\/HN, a lentiviral vector optimised for lung delivery, including CFTR protein expression, functional correction of CFTR defects and genomic integration site analysis in preparation for a first-in-human clinical trial.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Air\u2013liquid interface cultures of primary human bronchial epithelial cells (HBECs) from CF patients (F508del\/F508del), as well as a CFTR-deficient immortalised human lung epithelial cell line mimicking class I (CFTR-null) homozygous mutations, were used to assess transduction efficiency. Quantification methods included a novel proximity ligation assay for CFTR protein expression. For assessment of CFTR channel activity, Ussing chamber studies were conducted. The safety profile was assessed using integration site analysis and\n                      <jats:italic>in vitro<\/jats:italic>\n                      insertional mutagenesis studies.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      rSIV.F\/HN expressed CFTR and restored CFTR-mediated chloride currents to physiological levels in primary F508del\/F508del HBECs as well as in a class I cells. In contrast, the latter could not be achieved by small-molecule CFTR modulators, underscoring the potential of gene therapy for this mutation class. Combination of rSIV.F\/HN-CFTR with the potentiator ivacaftor showed a greater than additive effect. The genomic integration pattern showed no site predominance (frequency of occurrence \u226410%), and a low risk of insertional mutagenesis was observed in an\n                      <jats:italic>in vitro<\/jats:italic>\n                      immortalisation assay.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>The results underscore rSIV.F\/HN as a promising gene therapy vector for CF, providing a mutation-agnostic treatment option.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1183\/13993003.01683-2023","type":"journal-article","created":{"date-parts":[[2024,8,22]],"date-time":"2024-08-22T11:20:06Z","timestamp":1724325606000},"page":"2301683","update-policy":"https:\/\/doi.org\/10.1183\/ers-crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["Pharmacological and pre-clinical safety profile of rSIV.F\/HN, a hybrid lentiviral vector for cystic fibrosis gene therapy"],"prefix":"10.1183","volume":"65","author":[{"given":"Alena","family":"Moiseenko","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony","family":"Sinadinos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Sergijenko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyriel","family":"Pineault","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aarash","family":"Saleh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konradin","family":"Nekola","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalie","family":"Strang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anastasia","family":"Eleftheraki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. 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