Chronic infection and inflammation are the primary causes of declining lung function in people with cystic fibrosis (pwCF). Despite Kaftrio improving the quality of life in pwCF, clinical trials have shown variable responses to this drug formulation, that could be due to P. aeruginosa infection. P.aeruginosawas isolated from the sputum or bronchoalveolar lavage (BAL) samples, and nasal epithelial cells were collected using a noninvasive nasal brushing technique from CF patients carrying the F508del mutation.
The efficacy of CFTR modulators in primary nasal epithelial cells infected with clinical P. aeruginosa isolated from the corresponding pwCF was evaluated by measuring CFTR function. Moreover, the inflammatory response after infection with P. aeruginosa in primary nasal cells was evaluated by measuring the released pro-inflammatory cytokines and gene expression.
It has been observed a higher variability for the inflammatory response in primary nasal cells infected with P. aeruginosa isolated from the corresponding patient. Moreover, Kaftrio-mediated rescue of F508del-CFTR function is reduced by P. aeruginosa in primary nasal cells from pwCF. Interestingly, the reduction of F508del-CFTR activity was reduced in a strain-specific manner by 10 to 65%.
Understanding the role of infection and inflammatory response, that mimics the native status of CF airways, on mutated CFTR rescue by CFTR modulators should provide the basis for optimizing the prediction of clinical responses to CFTR modulators. In vitro studied of patient-specific responses to CFTR modulators under infection or inflammation in a relevant pre-clinical model using primary airway epithelial cells could enhance the prediction of clinical response.