Peptide CIGB-552 has a synergistic effect on CFTR-F508del when combined with elexacaftor/tezacaftor/ivacaftor triple therapy for cystic fibrosis.

Abstract

Background and purpose: Cystic fibrosis is an autosomal recessive disease caused by mutations in the CFTR gene, leading to progressive respiratory decline and reduced life expectancy. The most common mutation, CFTR-F508del, results in mislocalised and non-functional protein. Although triple therapy with elexacaftor/tezacaftor/ivacaftor (ETI) is prescribed for patients carrying this mutation, some biological defects remain unresolved. We previously identified COMMD1 as a potential therapeutic target, as its overexpression enhances CFTR-WT plasma membrane localisation. CIGB-552, a cell-penetrating peptide discovered in 2013, stabilises COMMD1. This study evaluates its therapeutic potential in cystic fibrosis.

Experimental approach: CIGB-552 was tested, with and without ETI, in CFBE and HEK cells stably expressing CFTR-WT or CFTR-F508del, and in primary human bronchial cells. CFTR function was assessed using YFP quenching and short-circuit current assays. Peptide uptake was evaluated using FITC-labelled CIGB-552 in submerged and air-liquid interface models. Plasma membrane density of CFTR was measured in CFBE CFTR-HA cells, and western blotting assessed CFTR maturation and COMMD1 expression.

Key results: CIGB-552 was non-toxic and preferentially entered CFBE CFTR-F508del cells rather than CFBE CFTR-WT cells, without altering COMMD1 expression or localisation. Although not a corrector or potentiator alone, CIGB-552 synergised with ETI, enhancing CFTR-F508del-mediated chloride efflux, confirmed in primary cells. CIGB-552 also increased YFP quenching of CFTR-WT and CFTR-G551D, in combination with ivacaftor. This effect required COMMD1.

Conclusions and implications: COMMD1 expression was necessary for CIGB-552 to affect CFTR function positively. Its synergy with the triple therapy offers a promising strategy for improving CF treatment.