WS15.04Elexacaftor/tezacaftor/ivacaftor CFTR modulators mitigates senescence in cystic fibrosis

Abstract

Objectives

Impaired CFTR function causes loss of chloride and bicarbonate efflux across epithelia, leading to dehydration of the airway surface liquid and increased oxidative stress.

Senescence is a cellular program characterized by irreversible cell cycle arrest largely triggered by oxidative stress. While in the short-term senescence serves as a protective mechanism to prevent damaged cells from proliferating and supporting wound healing, in the long term it may sustain the “inflammaging” process, increasing the risk of age-related disorders.

Thus, we sought to assess the role of senescence in Cystic Fibrosis (CF) pathophysiology and the effect of elexacaftor/tezacaftor/ivacaftor (ETI) treatment on this cellular program.

Methods

CF (F508del) and healthy control airway epithelia (hBEC/hNEC) with similar ages and culture passages, were compared.

Results

The p53 pathway was upregulated in CF along all the cell models tested. This was recapitulated by inhibiting CFTR-dependent chloride efflux with CFTR(inh)-172 in healthy hBECs, suggesting a direct role of CFTR function on the onset of senescence. The senescence-associated secretory phenotype (SASP) was found in CF-hBEC. CF airway epithelial cells were enlarged and flattened compared to healthy controls, showing an increased expression of cytoskeletal component vimentin and decreased lamin B1. CFTRinh-172 induced vimentin expression in healthy airway epithelial cells, whereas ETI treatment reduced both vimentin and lamin B1 levels in CF cells. Eventually, clinical data revealed that ETI therapy is able to reduce plasmatic levels of SASP-related soluble mediators in patients with CF.

Conclusion

Taken together, these results indicate that CF airway epithelia are generally senescent. Cellular senescence could be a major driver of the constitutive inflammation reported in CF lungs. ETI is able to mitigate senescence both in vitro and in vivo, highlighting potential benefits that may go far beyond the expected effects.