Rescue of the CFTR chloride channel with nonsense mutations is markedly improved under inflammatory conditions
Authors: Anna Borrelli, Arianna Venturini, Daniela Guidone, Martina De Santis, Enza Montemitro, Federico Alghisi,
Fabiana Ciciriello and Luis J.V. Galietta
Year: 2025
Sources: EUROPEAN RESPIRATORY JOURNAL
Abstract:
Loss of cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel function is the basic
defect in cystic fibrosis (CF), a genetic disease that particularly affects the respiratory system, with bacterial
infection and severe inflammation. People with CF carrying the most frequent mutation (F508del) or many
types of missense mutations can be efficiently treated with drugs, named correctors and potentiators, that
improve CFTR protein processing and channel activity. These treatments are ineffective on nonsense
mutations that lead to nonsense-mediated RNA decay (NMD) and CFTR protein truncation. We tested the
efficacy of a triple combination of small molecules including the readthrough agent ELX-02, the CFTR
corrector VX-809, and the eRF3A degrader CC-90009, on cultured airway epithelia from patients carrying
the G542X mutation. The treatment resulted in a significant but relatively modest (three-fold) increase in
CFTR function. Importantly, the efficacy of the triple drug combination was greatly amplified under
inflammatory conditions, i.e. by exposing the epithelia to interleukin (IL)-4 (15-fold increase) or to
IL-17A/tumour necrosis factor-α (nine-fold increase). Similar effects were also found in epithelia with the
W1282X mutation. The large rescue of CFTR function under inflammatory conditions was paralleled by
the appearance of full-length CFTR protein and by the increase in CFTR mRNA. The effect of
inflammatory stimuli could be mediated by enhanced translational readthrough and/or reduced NMD. Our
results suggest that rescue of CFTR with nonsense mutations could be more effective than expected
in vivo. Our findings may also lead to the identification of novel targets to correct the effect of nonsense
mutations in CF and other genetic diseases.
defect in cystic fibrosis (CF), a genetic disease that particularly affects the respiratory system, with bacterial
infection and severe inflammation. People with CF carrying the most frequent mutation (F508del) or many
types of missense mutations can be efficiently treated with drugs, named correctors and potentiators, that
improve CFTR protein processing and channel activity. These treatments are ineffective on nonsense
mutations that lead to nonsense-mediated RNA decay (NMD) and CFTR protein truncation. We tested the
efficacy of a triple combination of small molecules including the readthrough agent ELX-02, the CFTR
corrector VX-809, and the eRF3A degrader CC-90009, on cultured airway epithelia from patients carrying
the G542X mutation. The treatment resulted in a significant but relatively modest (three-fold) increase in
CFTR function. Importantly, the efficacy of the triple drug combination was greatly amplified under
inflammatory conditions, i.e. by exposing the epithelia to interleukin (IL)-4 (15-fold increase) or to
IL-17A/tumour necrosis factor-α (nine-fold increase). Similar effects were also found in epithelia with the
W1282X mutation. The large rescue of CFTR function under inflammatory conditions was paralleled by
the appearance of full-length CFTR protein and by the increase in CFTR mRNA. The effect of
inflammatory stimuli could be mediated by enhanced translational readthrough and/or reduced NMD. Our
results suggest that rescue of CFTR with nonsense mutations could be more effective than expected
in vivo. Our findings may also lead to the identification of novel targets to correct the effect of nonsense
mutations in CF and other genetic diseases.
Category: journals