Treatment of cystic fibrosis (CF) may be obtained by restoring the function of CFTR with mutation-specific drugs. A potentially alternative approach is to modulate the activity of other targets to stimulate CFTR-independent anion secretion or inhibit acidification. This approach could be essential for CF patients expressing undruggable CFTR mutants but could also be useful as an adjuvant therapy supporting the effect of CFTR rescue maneuvers.
Despite the increasing interest towards possible alternative targets such as TMEM16A, SLC26A9, SLC26A4, and ATP12A, their precise function and expression in the airways are largely unknown or controversial, and specific modulators are still lacking. For these reasons, this project aims to study the expression and the role of alternative targets in the airways and to develop tools and assays for therapeutic development.
The project involved the use of airway epithelial cells obtained from persons with cystic fibrosis of various ages, genotypes and clinical conditions and healthy controls using minimally invasive procedures (brushing of the mucous membrane of the nasal cavities).
Researchers applied spatial and functional imaging approaches in ex vivo samples (tissue microarrays of the airways, nasal brushings) and advanced in vitro models of the epithelial lining large and small airways.
They found intriguing differences in the expression levels, proximal-distal gradient, and cell type-specific localization in the airways of alternative targets. ATP12A and SLC26A4 were mainly localized in secretory cells and overexpressed under inflammatory conditions in vitro and ex vivo (CF and asthmatic patients). TMEM16A appeared with a very low expression in human bronchi and was undetectable in more distal regions. Interestingly, SLC26A9 was absent in most epithelial and glandular cells of the airways, except for rare epithelial cells (<1%) showing high expression. Researchers identified these cells as pulmonary neuroendocrine cells. Pharmacological dissection of alternative targets’ contribution to airway surface liquid (ASL) properties evidenced ATP12A as a major player in the regulation of ASL pH and viscosity, with its inhibition-producing effects considered beneficial for CF.
In conclusion, this study indicates that targeting the ATP12A proton pump could provide novel therapeutic opportunities for CF. To start the search for drug candidates in vitro models with functional expression of ATP12A were developed and an antisense-drug approach aimed at ATP12A suppression was designed.