Primary ciliary dyskinesia patient-specific model to study and treat ciliary dysfunction.

Respiratory primary ciliary dyskinesia (PCD) is a rare genetic ciliopathy characterized by anomalous mucociliary clearance caused by immotile or abnormal motion of the cilia lining the respiratory epithelium and/or by a severe reduction in the number of respiratory cilia. Restoration of ciliary function has not been possible as no causative treatment for PCD is available, resulting in a lifelong recurrent respiratory tract infection. Currently, there is still a lack of a proper in vitro model that (partially) recapitulates the in vivo situation of PCD patients. While these models resemble the different morphological and biochemical features of the original tissue and might be beneficial in the understanding and treatment of ciliary dysfunction in these patients. In the present study, we developed a novel PCD patient-specific model using human nasal airway epithelial cells and used ciliary beating frequency (CBF), rotation of 3D-apical out organoids, and bead movement as a functional readout for the ciliary activity. We observed patient-specific differences in CBF and rotation of 3D-apical out airway organoids, which were in agreement with the patients genetic mutation. Furthermore, we showed that 15 µm-sized polystyrene microbeads added on healthy epithelia moved in the same direction, consistent with coordinated beating of the underlying cilia, whereas beads added on PCD epithelia were immobile, suggesting an impairment of the mucociliary clearance function. Our findings suggest that our stem cell-based PCD model allows to study ciliary dysfunction and can be used for the identification, development, and high throughput drug screenings for the treatment of PCD.