CFTR modulators, such as ETI, have improved lung function in people with CF. However, even in those who respond well to treatment, chronic airway inflammation may persist and continue to contribute to lung damage. Furthermore, those who cannot take the modulators or who do not benefit from them continue to develop infections, inflammation and progressive deterioration in respiratory function.

In recent years, the hypothesis has emerged that this airway inflammation in CF is not merely a consequence of bacterial infections but also depends on the immune system. In particular, it is thought that the defect in the CFTR protein alters the functioning of the bone marrow (the tissue that produces all blood cells), causing it to generate immune cells predisposed to an excessive inflammatory response.

To test this hypothesis, the researchers will analyse haematopoietic stem cells, which give rise to all blood cells, and mesenchymal cells, which regulate their development within the bone marrow, from people with CF who are being treated with modulators, from people with CF who cannot take them or do not respond to the therapy, and from people without CF.
Using advanced molecular biology techniques, the researchers will investigate which genes and mechanisms regulate the behaviour of these cells to determine whether there are any alterations responsible for the production of overly reactive immune cells and whether the modulators are capable of correcting them.
Subsequently, strategies based on molecules that promote the physiological resolution of inflammation and on mesenchymal cells (either alone or in combination with ETI) will be evaluated to determine whether they are capable of mitigating inflammation and reprogramming the bone marrow to promote the production of immune cells with a more balanced inflammatory response.
Finally, the results obtained will be validated in CF animal models.

The ultimate aim is to understand whether chronic inflammation in CF is caused by a programming defect in the bone marrow and whether this defect can be corrected. The findings will deepen our understanding of inflammation in CF and could pave the way for more effective therapies capable of controlling inflammation, both for those taking CFTR modulators and for those who cannot benefit from them.