Deleterious effect of on F508del-CFTR rescued by elexacaftor/tezacaftor/ivacaftor is clinical strain-dependent in patient-derived nasal cells.

BACKGROUND

The triple cystic fibrosis transmembrane conductance regulator (CFTR) modulators combination elexacaftor/tezacaftor/ivacaftor (ETI) has been approved for people with cystic fibrosis (pwCF) bearing at least one allele. Despite the development of CFTR modulators having dramatically improved respiratory outcomes in pwCF, clinical studies have showed variable responses to this drug formulation. Of note, airway inflammation and bacterial colonisation persist in the upper and lower respiratory tract even in ETI-treated patients.

METHODS

We first tested the clinical exoproducts (EXO) of isolated from 15 CF patients in wild-type (WT) and F508del-CFTR CF bronchial epithelial (CFBE) cells. We were then prompted to evaluate the effects of EXO in patient-derived tissues. Therefore, we cultured primary nasal epithelial cells (HNECs) with EXO isolated from the corresponding pwCF to mimic the native status of CF airway.

RESULTS

We found that EXO variably decreased WT-, F508del- and ETI-dependent F508del-CFTR function and increased proinflammatory cytokines and reactive oxygen species (ROS) levels in a clinical strain-specific manner. Similarly, we observed a variable reduction of F508del-CFTR function in presence or absence of ETI and upregulation of proinflammatory cytokines and ROS levels. Interestingly, HNECs treated with EXO isolated from the corresponding donor and three different pwCF showed a variable reduction of ETI-dependent F508del-CFTR function mainly due to clinical strains with limited effect of patient background. Furthermore, we demonstrated that ETI pretreatment decreased the cytokines and ROS levels down to the levels of uninfected cells.

CONCLUSION

These preclinical studies suggest that screening of patient-specific response to CFTR modulators under infection/inflammation conditions could prove to be a valuable tool to enhance the prediction of clinical response.