DNAI1 mRNA in vitro treatment of DNAI1-deficient respiratory cells

Primary ciliary dyskinesia (PCD) is a group of rare genetic disorders characterised by the dysfunction of motile cilia, with the hallmark symptom of chronic mucopurulent airway disease. Recurrent airway infections can lead to irreversible lung damage that may progress to respiratory failure. There is no causal therapy for this genetic disease and evidence-based treatment is very limited. Recently, mRNA therapy has emerged as a promising therapeutic option to treat various diseases with high unmet medical need. DNAI1 is one of the most frequently affected genes in individuals with PCD leading to outer dynein arm defects with severely reduced ciliary beating. In this study, we aim to improve ciliary function in human nasal epithelial cells (hNECs) from PCD individuals with DNAI1- deficient motile cilia using a selective organ targeting (SORT) lipid nanoparticle (LNP) containing an optimized DNAI1 mRNA. hNECs were obtained by nasal brush biopsies and cultured at air–liquid interface. After differentiation into pseudostratified epithelium in vitro, cells were transfected basolaterally or via aerosol delivery with SORT-LNP- DNAI1 mRNA. We demonstrated successful transfection of DNAI1 -deficient multiciliated cells by restoration of ciliary beat frequency via high-speed video-microscopy analysis. Additionally, high-resolution immunofluorescence microscopy analysis with anti-DNAI1 antibodies confirmed the restored localization of DNAI1 and DNAI1-dependent proteins (e.g. DNAH5) in a subset of ciliary axonemes of DNAI1 individuals following SORT-LNP- DNAI1 mRNA treatment. In summary, we have demonstrated in vitro proof of concept for restoring cilia motility in hNECs from PCD patients with pathogenic DNAI1 variants treated with a mRNA therapy. Publication History Article published online: 26 February 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany