Chronic lung infections caused by Pseudomonas aeruginosa are common in people with cystic fibrosis and drive persistent inflammation and oxidative stress, leading to the accumulation of harmful molecules within cells. This process can impair the function of the CFTR protein and reduce the effectiveness of CFTR modulators, helping to explain why some people respond less well than others to treatments such as ETI. For this reason, there is a need to develop personalised anti-inflammatory therapies that can be used alongside CFTR modulators to enhance their efficacy.

This project will evaluate the potential of phosphodiesterase inhibitors (PDEi), a class of drugs already approved for other inflammatory diseases, to reduce inflammation and oxidative stress and, consequently, enhance the activity of CFTR modulators. 

Building on the findings of the previous FFC#4/2024 project, the researchers will test PDEi in nasal epithelial cells obtained from people with CF and exposed to products released by P. aeruginosa strains isolated from the same donors, recreating in the laboratory the conditions found in the CF lung. The experiments will determine whether PDEi can enhance the ability of CFTR modulators to restore the function of the mutated CFTR protein. The most promising results will then be validated in animal models in collaboration with the FFC Ricerca CFaCore Facility.

If these findings are confirmed, this approach could improve the effectiveness of CFTR modulators and help limit lung damage caused by chronic inflammation, particularly in people who respond poorly to currently available treatments or carry rare CFTR variants, paving the way for more personalized therapies. However, careful evaluation of the potential systemic side effects of PDEi and the identification of the safest and most effective dose for the CF lung will be essential.