CFTR modulators have transformed the treatment of cystic fibrosis, significantly improving the health and quality of life of many people with the disease. However, these drugs are still unable to fully restore the function of the CFTR protein, particularly in individuals with rare or difficult-to-treat mutations. In fact, part of the protein still fails to reach, or remain long enough at, the cell surface, where it regulates the transport of salt and water across the airway epithelium. This limits the effectiveness of current therapies and contributes to what is known as “residual disease.”

This project focuses on Protein Kinase D1 (PKD1), a protein involved in the cellular processes that regulate protein trafficking and membrane stability. Recent findings from the research group (FFC#3/2022) have shown that activating PKD1 through a specially designed peptide called PI3Kγ MP can increase the amount of CFTR protein present at the cell surface and prolong its functional activity, thereby enhancing the effects of CFTR modulators.

To test this hypothesis, the researchers will investigate how PKD1 regulates CFTR trafficking and stability using cell models and primary airway cells obtained from people with cystic fibrosis carrying both common and rare CFTR mutations. These studies will be carried out in collaboration with the FFC Ricerca Primary Cell Culture Facility.

The goal is to determine whether PKD1 could represent a novel therapeutic target to complement existing CFTR modulators, enhancing their efficacy and extending their benefits to a broader range of people with cystic fibrosis. Ultimately, this strategy could contribute to the development of more effective and personalized treatments.