{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T03:03:28Z","timestamp":1774926208859,"version":"3.50.1"},"reference-count":0,"publisher":"Oxford University Press (OUP)","license":[{"start":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T00:00:00Z","timestamp":1774915200000},"content-version":"am","delay-in-days":1,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Primary Ciliary Dyskinesia (PCD) is a genetically heterogeneous disorder leading to destructive airway disease with severe bronchiectasis and chronic lung failure in adulthood. Pathogenic variants in CCDC40 are associated with more severe reduction of lung function compared to most other PCD types. Currently, no therapies correcting the underlying disease mechanism are available. Here we investigate the efficacy of lipidoid nanoparticle-formulated mRNA encoding human CCDC40 (LNP-CCDC40-mRNA) as a corrective measure for structural and functional defects in vitro (human cells) and in vivo (zebrafish). Human nasal respiratory epithelial cells cultured at air-liquid-interface from five CCDC40-deficient individuals and a newly generated vertebrate animal model (ccdc40-\/- zebrafish) were treated with LNP-CCDC40-mRNA. CCDC40-deficient cells were analyzed by high-speed video microscopy and immunofluorescence microscopy. ccdc40-\/- zebrafish olfactory pit cilia were analyzed by high-speed video microscopy and fluid flow assays. Topical application of exogenous LNP-CCDC40-mRNA to CCDC40-deficient cells results in endogenous CCDC40 expression (10\u201374% of ciliated cells), enabling axonemal integration of CCDC40-associated proteins (CCDC39, GAS8\/DRC4, DNALI1). Consistently, ciliary beat frequencies were significantly increased in treated CCDC40-deficient cells and comparable to healthy control cells. Further, we showed improved ciliary transport of fluorescent particles. Injection or topical application of human LNP-CCDC40-mRNA to ccdc40-\/- zebrafish significantly increased ciliary motility and established directional flow in olfactory pits. We provide structural and functional evidence in vitro and in vivo for the biological efficacy of LNP-CCDC40-mRNA in CCDC40-deficient respiratory cells and zebrafish. Based on our results, an in vivo human study (Phase 1 trial) is planned in individuals with pathogenic variants in CCDC40.<\/jats:p>","DOI":"10.1093\/ajrcmb\/aanag034","type":"journal-article","created":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T12:46:19Z","timestamp":1774529179000},"source":"Crossref","is-referenced-by-count":0,"title":["mRNA therapy improves the composition and motility in\n                    <i>CCDC40-<\/i>\n                    deficient cilia\n                    <i>in vitro<\/i>\n                    and\n                    <i>in vivo<\/i>"],"prefix":"10.1093","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4092-0664","authenticated-orcid":false,"given":"Kai","family":"Wohlgemuth","sequence":"first","affiliation":[{"name":"University Children\u2019s Hospital Muenster Department of General Pediatrics, , Muenster,","place":["Germany"]}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4891-4448","authenticated-orcid":false,"given":"Margarida","family":"Rasteiro","sequence":"additional","affiliation":[{"name":"Universidade Nova de Lisboa iNOVA4Health, NOVA Medical School\/Faculdade de Ci\u00eancias M\u00e9dicas, NMS|FCM, , Lisboa,","place":["Portugal"]},{"name":"Universidade de Lisboa Instituto de Medicina Molecular Jo\u00e3o Lobo Antunes, Faculdade de Medicina, , Lisbon,","place":["Portugal"]}]},{"given":"Manish","family":"Aneja","sequence":"additional","affiliation":[{"name":"Ethris GmbH , Planegg,","place":["Germany"]}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6718-572X","authenticated-orcid":false,"given":"Catarina","family":"Bota","sequence":"additional","affiliation":[{"name":"University of Lisbon Department of Animal Biology, Faculty of Sciences, , Lisboa,","place":["Portugal"]},{"name":"Universidade de Lisboa Instituto de Medicina Molecular Jo\u00e3o Lobo Antunes, Faculdade de Medicina, , Lisbon,","place":["Portugal"]}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8303-100X","authenticated-orcid":false,"given":"Sandra","family":"Cindric","sequence":"additional","affiliation":[{"name":"University Children\u2019s Hospital Muenster Department of General Pediatrics, , Muenster,","place":["Germany"]}]},{"given":"Stefanie","family":"Freischem","sequence":"additional","affiliation":[{"name":"University Children\u2019s Hospital Muenster Department of General Pediatrics, , Muenster,","place":["Germany"]}]},{"given":"Sebastian","family":"George","sequence":"additional","affiliation":[{"name":"University Children\u2019s Hospital Muenster Department of General Pediatrics, , Muenster,","place":["Germany"]}]},{"given":"Gizem G\u00fcnes","family":"G\u00fcnsel","sequence":"additional","affiliation":[{"name":"Ethris GmbH , Planegg,","place":["Germany"]}]},{"given":"Seun","family":"Ishola","sequence":"additional","affiliation":[{"name":"Ethris GmbH , Planegg,","place":["Germany"]}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-4974-5540","authenticated-orcid":false,"given":"Julia","family":"Koenig","sequence":"additional","affiliation":[{"name":"University Children\u2019s Hospital Muenster Department of General Pediatrics, , Muenster,","place":["Germany"]}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5555-6941","authenticated-orcid":false,"given":"Rebekka","family":"Kubisch-Dohmen","sequence":"additional","affiliation":[{"name":"Ethris GmbH , Planegg,","place":["Germany"]}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-6891-1968","authenticated-orcid":false,"given":"Thomas","family":"Langenickel","sequence":"additional","affiliation":[{"name":"Ethris GmbH , Planegg,","place":["Germany"]}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1534-2105","authenticated-orcid":false,"given":"Niki Tomas","family":"Loges","sequence":"additional","affiliation":[{"name":"University Children\u2019s Hospital Muenster Department of General Pediatrics, , Muenster,","place":["Germany"]}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-1215-7685","authenticated-orcid":false,"given":"Miguel","family":"Lopes","sequence":"additional","affiliation":[{"name":"University of Lisbon Department of Animal Biology, Faculty of Sciences, , Lisboa,","place":["Portugal"]},{"name":"NOVA School of Science and Technology Department of Life Sciences, , Caparica,","place":["Portugal"]}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-8798-5257","authenticated-orcid":false,"given":"Verena","family":"Mummert","sequence":"additional","affiliation":[{"name":"Ethris GmbH , Planegg,","place":["Germany"]}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4355-353X","authenticated-orcid":false,"given":"Heike","family":"Olbrich","sequence":"additional","affiliation":[{"name":"University Children\u2019s Hospital Muenster Department of General Pediatrics, , Muenster,","place":["Germany"]}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8202-3809","authenticated-orcid":false,"given":"Petra","family":"Pennekamp","sequence":"additional","affiliation":[{"name":"University Children\u2019s Hospital Muenster Department of General Pediatrics, , Muenster,","place":["Germany"]}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6903-9187","authenticated-orcid":false,"given":"Telmo","family":"Pereira","sequence":"additional","affiliation":[{"name":"Universidade Nova de Lisboa iNOVA4Health, NOVA Medical School\/Faculdade de Ci\u00eancias M\u00e9dicas, NMS|FCM, , Lisboa,","place":["Portugal"]}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0840-6844","authenticated-orcid":false,"given":"Andreia L","family":"Pinto","sequence":"additional","affiliation":[{"name":"Universidade Nova de Lisboa iNOVA4Health, NOVA Medical School\/Faculdade de Ci\u00eancias M\u00e9dicas, NMS|FCM, , Lisboa,","place":["Portugal"]},{"name":"NOVA School of Science and Technology Department of Life Sciences, , Caparica,","place":["Portugal"]}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1571-2647","authenticated-orcid":false,"given":"Johanna","family":"Raidt","sequence":"additional","affiliation":[{"name":"University Children\u2019s Hospital Muenster Department of General Pediatrics, , Muenster,","place":["Germany"]}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9050-5675","authenticated-orcid":false,"given":"Carsten","family":"Rudolph","sequence":"additional","affiliation":[{"name":"Ethris GmbH , Planegg,","place":["Germany"]}]},{"given":"Adrian","family":"Ter Steege","sequence":"additional","affiliation":[{"name":"University Children\u2019s Hospital Muenster Department of General Pediatrics, , Muenster,","place":["Germany"]}]},{"given":"Drishti","family":"Valecha","sequence":"additional","affiliation":[{"name":"Ethris GmbH , Planegg,","place":["Germany"]}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6733-6356","authenticated-orcid":false,"given":"Susana S","family":"Lopes","sequence":"additional","affiliation":[{"name":"University of Lisbon cE3c\u2014Center for Ecology, Evolution and Environmental Changes & CHANGE\u2014Global Change and Sustainability. Department of Animal Biology, Faculty of Sciences, , Campo Grande, Edif\u00edcio C2, Lisboa, 1749-016,","place":["Portugal"]}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0282-6765","authenticated-orcid":false,"given":"Heymut","family":"Omran","sequence":"additional","affiliation":[{"name":"University Children\u2019s Hospital Muenster Department of General Pediatrics, , Muenster,","place":["Germany"]}]}],"member":"286","published-online":{"date-parts":[[2026,3,30]]},"container-title":["American Journal of Respiratory Cell and Molecular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/ajrcmb\/advance-article-pdf\/doi\/10.1093\/ajrcmb\/aanag034\/67660101\/aanag034.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ajrcmb\/advance-article-pdf\/doi\/10.1093\/ajrcmb\/aanag034\/67660101\/aanag034.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T02:11:28Z","timestamp":1774923088000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/ajrcmb\/advance-article\/doi\/10.1093\/ajrcmb\/aanag034\/8559764"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,30]]},"references-count":0,"URL":"https:\/\/doi.org\/10.1093\/ajrcmb\/aanag034","relation":{},"ISSN":["1535-4989"],"issn-type":[{"value":"1535-4989","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,30]]},"article-number":"aanag034"}}