CFTR modulators, such as ETI (elexacaftor, tezacaftor, ivacaftor), have greatly improved the treatment of cystic fibrosis (CF), but they only partially correct the CFTR protein defect, leaving many patients with a residual disease. Previous studies (FFC#3/2022, FFC#8/2018, FFC#25/2014 and FFC#23/2015) have suggested that boosting cAMP signaling might help improve the effectiveness of these treatments.

The researchers hypothesise that the cAMP-related protein named protein kinase D1 (PKD) is an important player in controlling how the CFTR channel reaches the cell surface.

The project aims to demonstrate that PKD1 activation can increase the effectiveness of modulators in correcting certain mutations (such as F508del) and help stabilize CFTR with rarer mutations (such as class VI) on the cell surface. 

The researchers will use imaging and biochemical techniques to explore how PKD1 influences the movement of CFTR to the cell surface and how it helps to keep it stable once on the membrane. In addition, primary bronchial/nasal epithelial cells from people with CF, provided by FFC Ricerca’s Primary Culture Service, will be used to test whether activation of PKD1 (e.g. with the previously identified PI3Kγ mimetic peptide) can enhance the function of mutant CFTR, either on its own or in combination with ETI.

This study may help to clarify the mechanisms regulating CFTR and assess whether targeting PKD1 could represent an effective strategy to enhance current therapies for cystic fibrosis.