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Journal of Cystic Fibrosis

Journal of Cystic Fibrosis

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Rescue by elexacaftor-tezacaftor-ivacaftor of the G1244E cystic fibrosis mutation's stability and gating defects are dependent on cell background

Published:1 May 2023 DOI: 10.1016/j.jcf.2022.12.005 PMID: 36543707
Valeria Tomati , Stefano Costa , Valeria Capurro , Emanuela Pesce , Cristina Pastorino , Mariateresa Lena , Elvira Sondo , Marco Di Duca , Federico Cresta , Simona Cristadoro , Federico Zara , Luis J.V. Galietta , Renata Bocciardi , Carlo Castellani , Maria Cristina Lucanto , Nicoletta Pedemonte

Abstract

Background

Cystic fibrosis is caused by mutations impairing expression, trafficking, stability and/or activity of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. The G1244E mutation causes a severe gating defect that it is not completely rescued by ivacaftor but requires the use of a second compound (a co-potentiator). Recently, it has been proposed that the corrector elexacaftor may act also as a co-potentiator.

Methods

By using molecular, biochemical and functional analyses we performed an in-depth characterization of the G1244E-CFTR mutant in heterologous and native cell models.

Results

Our studies demonstrate that processing and function of the mutant protein, as well as its pharmacological sensitivity, are markedly dependent on cell background. In heterologous expression systems, elexacaftor mainly acted on G1244E-CFTR as a co-potentiator, thus ameliorating the gating defect. On the contrary, in the native nasal epithelial cell model, elexacaftor did not act as a co-potentiator, but it increased mature CFTR expression possibly by improving mutant's defective stability at the plasma membrane.

Conclusions

Our study highlights the importance of the cell background in the evaluation of CFTR modulator effects. Further, our results draw attention to the need for the development of novel potentiators having different mechanisms with respect to ivacaftor to improve channel activity for mutants with severe gating defect.

Substances (14)

Materials Related products
Procduct Name CAS Molecular Formula Supplier Price
Ivacaftor 873054-44-5 C24H28N2O3 338 suppliers $8.00-$25200.00
Ivacaftor 873054-44-5 C24H28N2O3 338 suppliers $8.00-$25200.00
Ivacaftor 873054-44-5 C24H28N2O3 338 suppliers $8.00-$25200.00
Ivacaftor 873054-44-5 C24H28N2O3 338 suppliers $8.00-$25200.00
Lumacaftor (VX-809) 936727-05-8 C24H18F2N2O5 273 suppliers $8.00-$7304.85
Lumacaftor (VX-809) 936727-05-8 C24H18F2N2O5 273 suppliers $8.00-$7304.85
Lumacaftor (VX-809) 936727-05-8 C24H18F2N2O5 273 suppliers $8.00-$7304.85
Lumacaftor (VX-809) 936727-05-8 C24H18F2N2O5 273 suppliers $8.00-$7304.85
Tezacaftor 1152311-62-0 C26H27F3N2O6 208 suppliers $9.00-$1600.00
Tezacaftor 1152311-62-0 C26H27F3N2O6 208 suppliers $9.00-$1600.00

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