- •Expression and pharmacological rescue of G1244E-CFTR depend on cell background.
- •In heterologous models elexacaftor mainly acts on G1244E-CFTR as a co-potentiator.
- •In native cells, elexacaftor increases mature CFTR expression.
- •Co-potentiators are needed to improve channel activity of G1244E-CFTR.
- •Development of novel co-potentiating drugs will help rescue of G1244E-CFTR.
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.
By using molecular, biochemical and functional analyses we performed an in-depth characterization of the G1244E-CFTR mutant in heterologous and native cell models.
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.
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.
To read this article in full you will need to make a payment
Purchase one-time access:Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
One-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:Subscribe to Journal of Cystic Fibrosis
Already a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
- Cystic fibrosis genetics: from molecular understanding to clinical application.Nat Rev Genet. 2015; 16: 45-56
- CFTR Modulators: the Changing Face of Cystic Fibrosis in the Era of Precision Medicine.Front Pharmacol. 2019; 10: 1662
- Cystic fibrosis: a clinical view.Cell Mol Life Sci. 2017; 74: 129-140
- Structure, Gating, and Regulation of the Cftr Anion Channel.Physiol Rev. 2019; 99: 707-738
- CFTR structure, stability, function and regulation.Biol Chem. 2019; 400: 1359-1370
- Progress in therapies for cystic fibrosis.Lancet Respir Med. 2016; 4: 662-674
- 1154insTC is not a rare CFTR mutation.Am J Med Genet A. 2003; 120A: 294-295
- Lukacs GL. C-terminal truncations destabilize the cystic fibrosis transmembrane conductance regulator without impairing its biogenesis. A novel class of mutation.J Biol Chem. 1999; 274: 21873-21877
- From CFTR biology toward combinatorial pharmacotherapy: expanded classification of cystic fibrosis mutations.Mol Biol Cell. 2016; 27: 424-433
- Peripheral protein quality control removes unfolded CFTR from the plasma membrane.Science. 2010; 329: 805-810
- CFTR modulator theratyping: current status, gaps and future directions.J Cyst Fibros. 2019; 18: 22-34
- Structure-guided combination therapy to potently improve the function of mutant CFTRs.Nat Med. 2018; 24: 1732-1742
- Mechanism of CFTR correction by type I folding correctors.Cell. 2022; 185 (e11): 158-168
- Allosteric folding correction of F508del and rare CFTR mutants by elexacaftor-tezacaftor-ivacaftor (Trikafta) combination.JCI Insight. 2020; 5
- Molecular structures reveal synergistic rescue of Delta508 CFTR by Trikafta modulators.Science. 2022; 378: 284-290
- Partial Rescue of F508del-CFTR Stability and Trafficking Defects by Double Corrector Treatment.Int J Mol Sci. 2021; 22
- Efficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: a double-blind, randomised, phase 3 trial.Lancet. 2019; 394: 1940-1948
- Elexacaftor-Tezacaftor-Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele.N Engl J Med. 2019; 381: 1809-1819
- Therapeutic approaches to CFTR dysfunction: from discovery to drug development.J Cyst Fibros. 2018; 17: S14-S21
- Peripheral Protein Quality Control as a Novel Drug Target for CFTR Stabilizer.Front Pharmacol. 2018; 9: 1100
- Screening for non-delta F508 mutations in five exons of the cystic fibrosis transmembrane conductance regulator (CFTR) gene in Italy.Am J Hum Genet. 1991; 48: 1127-1132
- Regulation by ATP and ADP of CFTR chloride channels that contain mutant nucleotide-binding domains.Science. 1992; 257: 1701-1704
- Structural mechanisms of CFTR function and dysfunction.J Gen Physiol. 2018; 150: 539-570
- Ivacaftor potentiation of multiple CFTR channels with gating mutations.J Cyst Fibros. 2012; 11: 237-245
- Mutation-specific dual potentiators maximize rescue of CFTR gating mutants.J Cyst Fibros. 2020; 19: 236-244
- The L467F-F508del Complex Allele Hampers Pharmacological Rescue of Mutant CFTR by Elexacaftor/Tezacaftor/Ivacaftor in Cystic Fibrosis Patients: the Value of the Ex Vivo Nasal Epithelial Model to Address Non-Responders to CFTR-Modulating Drugs.Int J Mol Sci. 2022; 23
- Thiazolidinone CFTR inhibitor identified by high-throughput screening blocks cholera toxin-induced intestinal fluid secretion.J Clin Invest. 2002; 110: 1651-1658
- Rescue of multiple class II CFTR mutations by elexacaftor+ tezacaftor+ivacaftor mediated in part by the dual activities of Elexacaftor as both corrector and potentiator.Eur Respir J. 2020;
- Elexacaftor co-potentiates the activity of F508del and gating mutants of CFTR.J Cyst Fibros. 2021; 20: 895-898
- Pharmacological Inhibition of the Ubiquitin Ligase RNF5 Rescues F508del-CFTR in Cystic Fibrosis Airway Epithelia.Cell Chem Biol. 2018; 25 (e8): 891-905
- The future of cystic fibrosis care: a global perspective.Lancet Respir Med. 2020; 8: 65-124
- Influence of cell background on pharmacological rescue of mutant CFTR.Am J Physiol Cell Physiol. 2010; 298: C866-C874
- A multimodal iPSC platform for cystic fibrosis drug testing.Nat Commun. 2022; 13: 4270
- Recent progress in translational cystic fibrosis research using precision medicine strategies.Journal of Cystic Fibrosis. 2018; 17: S52-S60
- Established and novel human translational models to advance cystic fibrosis research, drug discovery, and optimize CFTR-targeting therapeutics.Curr Opin Pharmacol. 2022; 64102210
- Revisiting CFTR Interactions: old Partners and New Players.Int J Mol Sci. 2021; 22
- RNF5, DAB2 and Friends: novel Drug Targets for Cystic Fibrosis.Curr Pharm Des. 2017; 23: 176-186
- DeltaF508 CFTR processing correction and activity in polarized airway and non-airway cell monolayers.Pulm Pharmacol Ther. 2010; 23: 268-278
- Discovery of a picomolar potency pharmacological corrector of the mutant CFTR chloride channel.Sci Adv. 2020; 6: eaay9669
- Combination potentiator ('co-potentiator') therapy for CF caused by CFTR mutants, including N1303K, that are poorly responsive to single potentiators.J Cyst Fibros. 2018; 17: 595-606
- In vitro Methods for the Development and Analysis of Human Primary Airway Epithelia.Front Pharmacol. 2018; 9: 1176
- Dual SMAD Signaling Inhibition Enables Long-Term Expansion of Diverse Epithelial Basal Cells.Cell Stem Cell. 2016; 19: 217-231
- Small-molecule correctors of defective DeltaF508-CFTR cellular processing identified by high-throughput screening.J Clin Invest. 2005; 115: 2564-2571
- Rescue of the mutant CFTR chloride channel by pharmacological correctors and low temperature analyzed by gene expression profiling.Am J Physiol Cell Physiol. 2011; 301: C872-C885
- High-throughput screening identifies FAU protein as a regulator of mutant cystic fibrosis transmembrane conductance regulator channel.J Biol Chem. 2018; 293: 1203-1217
Published online: December 19, 2022
Accepted: December 13, 2022
Received in revised form: November 23, 2022
Received: September 8, 2022
Publication stageIn Press Corrected Proof
© 2022 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.