ArticleAmerican journal of respiratory cell and molecular biology2026
mRNA therapy improves the composition and motility in CCDC40-deficient cilia in vitro and in vivo.
Kai Wohlgemuth, Margarida Rasteiro, Manish Aneja, Catarina Bota, Sandra Cindric, Stefanie Freischem, Sebastian George, Gizem Günes Günsel, Seun Ishola, Julia Koenig and 15 more
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In one paragraphArticle in American journal of respiratory cell and molecular biology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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5 · Who and what moneyAuthors and funding
25 authors.
Kai WohlgemuthDepartment of General Pediatrics, University Children's Hospital Muenster, Muenster, Germany.ORCID 0000-0003-4092-0664 Margarida RasteiroiNOVA4Health, NOVA Medical School/Faculdade de Ciências Médicas, NMS|FCM, Universidade Nova de Lisboa, Lisboa, Portugal.ORCID 0000-0002-4891-4448 Manish AnejaEthris GmbH, Planegg, Germany.
Catarina BotaInstituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.ORCID 0000-0002-6718-572X Sandra CindricDepartment of General Pediatrics, University Children's Hospital Muenster, Muenster, Germany.ORCID 0000-0002-8303-100X Stefanie FreischemDepartment of General Pediatrics, University Children's Hospital Muenster, Muenster, Germany.
Sebastian GeorgeDepartment of General Pediatrics, University Children's Hospital Muenster, Muenster, Germany.
Gizem Günes GünselEthris GmbH, Planegg, Germany.
Seun IsholaEthris GmbH, Planegg, Germany.
Julia KoenigDepartment of General Pediatrics, University Children's Hospital Muenster, Muenster, Germany.ORCID 0009-0002-4974-5540 Niki Tomas LogesDepartment of General Pediatrics, University Children's Hospital Muenster, Muenster, Germany.ORCID 0000-0002-1534-2105 Miguel LopesDepartment of Animal Biology, Faculty of Sciences, University of Lisbon, Lisboa, Portugal.ORCID 0009-0008-1215-7685 Heike OlbrichDepartment of General Pediatrics, University Children's Hospital Muenster, Muenster, Germany.ORCID 0000-0003-4355-353X Petra PennekampDepartment of General Pediatrics, University Children's Hospital Muenster, Muenster, Germany.ORCID 0000-0002-8202-3809 Telmo PereiraiNOVA4Health, NOVA Medical School/Faculdade de Ciências Médicas, NMS|FCM, Universidade Nova de Lisboa, Lisboa, Portugal.ORCID 0000-0002-6903-9187 Andreia L PintoiNOVA4Health, NOVA Medical School/Faculdade de Ciências Médicas, NMS|FCM, Universidade Nova de Lisboa, Lisboa, Portugal.ORCID 0000-0002-0840-6844 Johanna RaidtDepartment of General Pediatrics, University Children's Hospital Muenster, Muenster, Germany.ORCID 0000-0002-1571-2647 Adrian Dorißen Ter SteegeDepartment of General Pediatrics, University Children's Hospital Muenster, Muenster, Germany.
Drishti ValechaEthris GmbH, Planegg, Germany.
Susana S LopescE3c - Center for Ecology, Evolution and Environmental Changes & CHANGE - Global Change and Sustainability, Department of Animal Biology, Faculty of Sciences, University of Lisbon, Lisboa, Portugal.ORCID 0000-0002-6733-6356 Heymut OmranDepartment of General Pediatrics, University Children's Hospital Muenster, Muenster, Germany.ORCID 0000-0003-0282-6765 Funding
Care-for-Rare FoundationDeutsche Forschungsgemeinschaft KFO/326Deutsche Forschungsgemeinschaft OL450/1Deutsche Forschungsgemeinschaft OM6/10Deutsche Forschungsgemeinschaft OM6/11Deutsche Forschungsgemeinschaft OM6/14Deutsche Forschungsgemeinschaft OM6/7Deutsche Forschungsgemeinschaft OM6/8ETHRIS ZF4610102SK8European Union Horizon 2020 research and innovation 811087Eva Luise Köhler ResearchFederal Ministry for Economic Affairs and Climate Action 16LW0647KFederal Ministry for Economic Affairs and Climate Action 16LW0648Federal Ministry of Research, Technology and SpaceInnovative Medizinische Forschung LO 1 2 15 17Interdisziplinäres Zentrum für Klinische Forschung Muenster OM2/010/20Interdisziplinäres Zentrum für Klinische Forschung Muenster OM2/015/16Maratona da Saúde senior prize on Rare Diseases 2021
6 · The paper itselfAbstract
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 a 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 an air-liquid interface from 5 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%-74% 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 were comparable to those of 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.
Indexed as
CiliaKartagener SyndromeRNA, MessengerAnimalsDisease Models, AnimalEpithelial CellsHumansNanoparticlesZebrafishRNA, Messengerlipidoid nanoparticlemRNA-therapyprimary ciliary dyskinesiarespiratory epithelial cellszebrafish
Identifiers
PMID42089334
PMCPMC13519353
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