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ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Pharmacology of Ion Channels and Channelopathies
Volume 15 - 2024 |
doi: 10.3389/fphar.2024.1494327
This article is part of the Research Topic Epithelial Transport: from fluid movement toward system organization View all articles
Pharmacological rescue of the G85E CFTR variant by preclinical and approved modulators
Provisionally accepted- 1 Giannina Gaslini Institute (IRCCS), Genoa, Liguria, Italy
- 2 Telethon Institute of Genetics and Medicine (TIGEM), Naples, Campania, Italy
- 3 P.O. San Liberatore, Atri, Italy, Atri, Italy
- 4 Meyer Children's Hospital IRCCS, Cystic Fibrosis Regional Reference Center, Florence, Italy, Florence, Italy
- 5 Azienda Ospedaliera Universitaria Policlinico G. Martino, Messina, Italy, Messina, Italy
- 6 Italian Institute of Technology (IIT), Genova, Liguria, Italy
- 7 Lab. of Molecular Genetics, Giannina Gaslini Institute (IRCCS), Genoa, Italy
Cystic Fibrosis (CF) is a genetic disease due to loss-of-function mutations of the CFTR channel. F508del is the most frequent mutation (70% of alleles in Italy), while other mutations have much lower frequency. Among them, G85E (0.4 % frequency globally, 1.13 % in Italy) emerges as a mutation characterized by a severe CFTR folding and trafficking defect. To investigate the pharmacological responsiveness of the G85E-CFTR variant, we performed a functional and biochemical characterization in heterologous expression systems and ex vivo models based on patient-derived human nasal epithelial cells (HNEC). Our study demonstrated that treatment of primary airway cells with elexacaftor and tezacaftor causes a significant (although modest) rescue of CFTR function, that reaches 15-25% of the activity measured in non-CF epithelia. A detrimental effect of chronic treatment with ivacaftor, further limiting G85E rescue, was also observed. A higher rescue of CFTR function, up to 25-35% of the normal CFTR activity, with no evidence of negative effects upon chronic potentiator treatment, can be achieved by combining elexacaftor with ARN23765, a novel type 1 corrector endowed with very high potency. Importantly, dose-response relationships suggest that G85E might alter the binding of type 1 correctors, possibly affecting their affinity for the target. In conclusion, our studies suggest that novel combinations of modulators, endowed with higher efficacy leading to increased rescue of G85E-CFTR, are needed to improve the clinical benefit in patients for this variant.
Keywords: CFTR, correctors, Gating, theratyping, nasal, modulators
Received: 10 Sep 2024; Accepted: 31 Oct 2024.
Copyright: © 2024 Tomati, Capurro, Pesce, Pastorino, Sondo, Lena, Borrelli, Cresta, Pantano, Collini, Ripani, Terlizzi, Fevola, Costa, Lucanto, Zara, Bandiera, Bocciardi, Castellani, Galietta and Pedemonte. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Nicoletta Pedemonte, Lab. of Molecular Genetics, Giannina Gaslini Institute (IRCCS), Genoa, Italy
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