Cystic fibrosis (CF) is an inherited disorder caused by mutations in the gene encoding for the cystic fibrosis transmembrane conductance regulator (CFTR) protein, an ATP-gated chloride channel expressed on the apical surface of airway epithelial cells. CFTR absence/dysfunction results in defective ion transport and subsequent airway surface liquid dehydration that severely compromise the airway microenvironment. Noxious agents and pathogens are entrapped inside the abnormally thick mucus layer and establish a highly inflammatory environment, ultimately leading to lung damage. Since chronic airway inflammation plays a crucial role in CF pathophysiology, several studies have investigated the mechanisms responsible for the altered inflammatory/immune response that, in turn, exacerbates the epithelial dysfunction and infection susceptibility in CF patients. In this review, we address the evidence for a critical role of dysfunctional inflammation in lung damage in CF and discuss current therapeutic approaches targeting this condition, as well as potential new treatments that have been developed recently. Traditional therapeutic strategies have shown several limitations and limited clinical benefits. Therefore, many efforts have been made to develop alternative treatments and novel therapeutic approaches, and recent findings have identified new molecules as potential anti-inflammatory agents that may exert beneficial effects in CF patients. Furthermore, the potential anti-inflammatory properties of CFTR modulators, a class of drugs that directly target the molecular defect of CF, also will be critically reviewed. Finally, we also will discuss the possible impact of SARS-CoV-2 infection on CF patients, with a major focus on the consequences that the viral infection could have on the persistent inflammation in these patients.

Cystic fibrosis (CF), the most common genetic disease among the Caucasian population, is caused by mutations in the gene encoding for the CF transmembrane conductance regulator (CFTR), a chloride epithelial channel whose dysfunction results in severe airway obstruction and inflammation, eventually leading to respiratory failure. The discovery of the CFTR gene in 1989 provided new insights into the basic genetic defect of CF and allowed the study of potential therapies targeting the aberrant protein. In recent years, the approval of “CFTR modulators”, the first molecules designed to selectively target the underlying molecular defects caused by specific CF-causing mutations, marked the beginning of a new era in CF treatment. These drugs have been demonstrated to significantly improve lung function and ameliorate the quality of life of many patients, especially those bearing the most common CFTR mutatant F508del. However, a substantial portion of CF subjects, accounting for ~20% of the European CF population, carry rare CFTR mutations and are still not eligible for CFTR modulator therapy, partly due to our limited understanding of the molecular defects associated with these genetic alterations. Thus, the implementation of models to study the phenotype of these rare CFTR mutations and their response to currently approved drugs, as well as to compounds under research and clinical development, is of key importance. The purpose of this review is to summarize the current knowledge on the potential of CFTR modulators in rescuing the function of rare CF-causing CFTR variants, focusing on both investigational and clinically approved molecules.