Nasal epithelial cells as model for cystic fibrosis

Abstract

Cystic fibrosis (CF) is an inheritable disease in which the chloride channel CFTR does not function properly. This leads to the formation of thick, sticky mucus, causing problems in multiple organs, particularly in the lungs, and can result in premature death. CF is caused by a DNA mutation in the CFTR gene. Approximately 80% of individuals with CF are eligible for CFTR-repairing drugs, depending on their mutation type. However, due to the exorbitant cost of these drugs, only 12% of people with CF receive this therapy. The effectiveness of (new) drugs for CF can be tested in the lab by modeling water and salt transport in cultured cells. In this thesis, we developed protocols for culturing nasal cells and nasal organoids (3D mini-organs), obtained from a simple nose brush, as model for CF. We utilized these nasal organoids in the forskolin-induced swelling (FIS) assay to predict individual responses to the currently available drugs. Additionally, we used the nasal organoids to identify drugs that activate alternative chloride channels other than CFTR. This could serve as an alternative therapy to restore salt and water transport, irrespective of the type of mutation. We discovered drugs that induce fluid transport in the nasal organoids, but it remains unknown by which ion channel they operate. Furthermore, we investigated the differences between cultured nasal and bronchial cells to understand the representativeness of nasal cells for the lower airways, where most symptoms in people with CF occur.