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Research Advances on Cystic Fibrosis and CFTR Protein
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Research Advances on Cystic Fibrosis and CFTR Protein

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (20 December 2024) | Viewed by 9856

Special Issue Editor

Dr. Debora Baroni

E-Mail Website
Guest Editor
Istituto di Biofisica (IBF), Consiglio Nazionale delle Ricerche (CNR), Via De Marini 6, 16149 Genova, Italy
Interests: protein processing; protein post-translational modifications; CFTR modulators; CFTR expression and functional assays; epithelial tissue models
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues, 

Cystic fibrosis (CF) is a multisystem recessive genetic disease which causes severe chronic sinopulmonary dysfunction and loss of pancreatic exocrine function. Since its first description, technological developments and basic scientific research have allowed great advancements to be made in the treatment of CF. High-throughput screening assays culminated in the discovery of CFTR modulators, highly effective small molecules for groups of patients with specific CF genotypes. Gene and stem cell therapies, as well as pharmacologic strategies aimed to modulate alternative ion channels or transporters, are also under development to further enlarge the cohort of treatable patients. However, finding a definitive cure for all patients is still challenging because of the heterogeneity of CFTR mutations and phenotypes involved, as well as other individual factors that limit the effectiveness of the therapy.

In this Special Issue, we would like to focus on all advancements regarding CF and aspects of CFTR protein research that are under development to definitively defeat the disease, including:

  • Novel CFTR- and non-CFTR-modulating therapeutic approaches;
  • Non-pharmacological strategies to cope with the effects of the disease and maintain or improve their quality of life;
  • New clinical intervention strategies for managing the disease;
  • Newer drugs for symptomatic improvement;
  • Upcoming personalized medicine concepts for CF.

Dr. Debora Baroni
Guest Editor

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

  • cystic fibrosis
  • CFTR modulators, stabilizers, amplifiers and proteostasis modulators
  • read-through agents and NMD inhibitors
  • alternative channel targets
  • gene editing
  • RNA therapeutics
  • stem cell approaches
  • non-drug treatments for cystic fibrosis
  • airway clearance techniques and pulmonary rehabilitation strategies
  • personalized medicine

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Published Papers (5 papers)

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Research

16 pages, 3186 KiB  
Article
VX-770, Cact-A1, and Increased Intracellular cAMP Have Distinct Acute Impacts upon CFTR Activity
by Heidi J. Nick, Sarah E. Christeson and Preston E. Bratcher
Int. J. Mol. Sci. 2025, 26(2), 471; https://doi.org/10.3390/ijms26020471 - 8 Jan 2025
Viewed by 676
Abstract
The cystic fibrosis transmembrane conductance regulator (CFTR) is an anion channel that is dysfunctional in individuals with cystic fibrosis (CF). The permeability of CFTR can be experimentally manipulated though different mechanisms, including activation via inducing the phosphorylation of residues in the regulatory domain [...] Read more.
The cystic fibrosis transmembrane conductance regulator (CFTR) is an anion channel that is dysfunctional in individuals with cystic fibrosis (CF). The permeability of CFTR can be experimentally manipulated though different mechanisms, including activation via inducing the phosphorylation of residues in the regulatory domain as well as altering the gating/open probability of the channel. Phosphorylation/activation of the channel is achieved by exposure to compounds that increase intracellular cAMP, with forskolin and IBMX commonly used for this purpose. Cact-A1 is a unique CFTR activator that does not increase intracellular cAMP, and VX-770 (ivacaftor) is a CFTR potentiator that is used experimentally and therapeutically to increase the open probability of the channel. Using primary human nasal epithelial cell (HNEC) cultures and Fischer rat thyroid (FRT) epithelial cells exogenously expressing functional CFTR, we examined the impact of VX-770, Cact-A1, and forskolin/IBMX on CFTR activity during analysis in an Ussing chamber. Relative contributions of these compounds to maximal CFTR activity were dependent on order of exposure, the presence of chemical and electrical gradients, the level of constitutive CFTR function, and the cell model tested. Increasing intracellular cAMP appeared to change cellular functions outside of CFTR activity that resulted in alterations in the drive for chloride through CFTR. These results demonstrate that one can utilize combinations of small-molecule CFTR activators and potentiators to provide detailed characterization of CFTR-mediated ion transport in primary HNECs and properties of these modulators in both primary HNECs and FRT cells. Future studies using these approaches may assist in the identification of novel defects in CFTR function and the identification of modulators with unique impacts on CFTR-mediated ion transport. Full article
(This article belongs to the Special Issue Research Advances on Cystic Fibrosis and CFTR Protein)
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13 pages, 1194 KiB  
Article
Analysis of CFTR mRNA and Protein in Peripheral Blood Mononuclear Cells via Quantitative Real-Time PCR and Western Blot
by Alexander Schnell, Stephanie Tamm, Silke Hedtfeld, Claudio Rodriguez Gonzalez, Andre Hoerning, Nico Lachmann, Frauke Stanke, Anna-Maria Dittrich and Antje Munder
Int. J. Mol. Sci. 2024, 25(12), 6367; https://doi.org/10.3390/ijms25126367 - 8 Jun 2024
Viewed by 2689
Abstract
The Cystic Fibrosis Conductance Transmembrane Regulator gene encodes for the CFTR ion channel, which is responsible for the transport of chloride and bicarbonate across the plasma membrane. Mutations in the gene result in impaired ion transport, subsequently leading to perturbed secretion in all [...] Read more.
The Cystic Fibrosis Conductance Transmembrane Regulator gene encodes for the CFTR ion channel, which is responsible for the transport of chloride and bicarbonate across the plasma membrane. Mutations in the gene result in impaired ion transport, subsequently leading to perturbed secretion in all exocrine glands and, therefore, the multi-organ disease cystic fibrosis (CF). In recent years, several studies have reported on CFTR expression in immune cells as demonstrated by immunofluorescence, flow cytometry, and immunoblotting. However, these data are mainly restricted to single-cell populations and show significant variation depending on the methodology used. Here, we investigated CFTR transcription and protein expression using standardized protocols in a comprehensive panel of immune cells. Methods: We applied a high-resolution Western blot protocol using a combination of highly specific monoclonal CFTR antibodies that have been optimized for the detection of CFTR in epithelial cells and healthy primary immune cell subpopulations sorted by flow cytometry and used immortalized cell lines as controls. The specificity of CFTR protein detection was controlled by peptide competition and enzymatic Peptide-N-Glycosidase-F (PNGase) digest. CFTR transcripts were analyzed using quantitative real-time PCR and normalized to the level of epithelial T84 cells as a reference. Results: CFTR mRNA expression could be shown for primary CD4+ T cells, NK cells, as well as differentiated THP-1 and Jurkat T cells. In contrast, we failed to detect CFTR transcripts for CD14+ monocytes and undifferentiated THP-1 cells, as well as for B cells and CD8+ T cells. Prominent immunoreactive bands were detectable by immunoblotting with the combination of four CFTR antibodies targeting different epitopes of the CFTR protein. However, in biosamples of non-epithelial origin, these CFTR-like protein bands could be unmasked as false positives through peptide competition or PNGase digest, meaning that the observed mRNA transcripts were not necessarily translated into CFTR proteins, which could be detected via immunoblotting. Our results confirm that mRNA expression in immune cells is many times lower than in that cells of epithelial origin. The immunoreactive signals in immune cells turned out to be false positives, and may be provoked by the presence of a high-affinity protein with a similar epitope. Non-specific binding (e.g., Fab-interaction with glycosyl branches) might also contribute to false positive signals. Our findings highlight the necessity of accurate controls, such as CFTR-negative cells, as well as peptide competition and glycolytic digest in order to identify genuine CFTR protein by immunoblotting. Our data suggest, furthermore, that CFTR protein expression data from techniques such as histology, for which the absence of a molecular weight or other independent control prevents the unmasking of false positive immunoreactive signals, must be interpreted carefully as well. Full article
(This article belongs to the Special Issue Research Advances on Cystic Fibrosis and CFTR Protein)
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22 pages, 10387 KiB  
Article
Loss of CFTR Reverses Senescence Hallmarks in SARS-CoV-2 Infected Bronchial Epithelial Cells
by Flavia Merigo, Anna Lagni, Federico Boschi, Paolo Bernardi, Anita Conti, Roberto Plebani, Mario Romano, Claudio Sorio, Virginia Lotti and Andrea Sbarbati
Int. J. Mol. Sci. 2024, 25(11), 6185; https://doi.org/10.3390/ijms25116185 - 4 Jun 2024
Viewed by 1635
Abstract
SARS-CoV-2 infection has been recently shown to induce cellular senescence in vivo. A senescence-like phenotype has been reported in cystic fibrosis (CF) cellular models. Since the previously published data highlighted a low impact of SARS-CoV-2 on CFTR-defective cells, here we aimed to investigate [...] Read more.
SARS-CoV-2 infection has been recently shown to induce cellular senescence in vivo. A senescence-like phenotype has been reported in cystic fibrosis (CF) cellular models. Since the previously published data highlighted a low impact of SARS-CoV-2 on CFTR-defective cells, here we aimed to investigate the senescence hallmarks in SARS-CoV-2 infection in the context of a loss of CFTR expression/function. We infected WT and CFTR KO 16HBE14o-cells with SARS-CoV-2 and analyzed both the p21 and Ki67 expression using immunohistochemistry and viral and p21 gene expression using real-time PCR. Prior to SARS-CoV-2 infection, CFTR KO cells displayed a higher p21 and lower Ki67 expression than WT cells. We detected lipid accumulation in CFTR KO cells, identified as lipolysosomes and residual bodies at the subcellular/ultrastructure level. After SARS-CoV-2 infection, the situation reversed, with low p21 and high Ki67 expression, as well as reduced viral gene expression in CFTR KO cells. Thus, the activation of cellular senescence pathways in CFTR-defective cells was reversed by SARS-CoV-2 infection while they were activated in CFTR WT cells. These data uncover a different response of CF and non-CF bronchial epithelial cell models to SARS-CoV-2 infection and contribute to uncovering the molecular mechanisms behind the reduced clinical impact of COVID-19 in CF patients. Full article
(This article belongs to the Special Issue Research Advances on Cystic Fibrosis and CFTR Protein)
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14 pages, 2361 KiB  
Article
Comprehensive Assessment of CFTR Modulators’ Therapeutic Efficiency for N1303K Variant
by Anna Efremova, Nataliya Kashirskaya, Stanislav Krasovskiy, Yuliya Melyanovskaya, Maria Krasnova, Diana Mokrousova, Nataliya Bulatenko, Elena Kondratyeva, Oleg Makhnach, Tatiana Bukharova, Rena Zinchenko, Sergey Kutsev and Dmitry Goldshtein
Int. J. Mol. Sci. 2024, 25(5), 2770; https://doi.org/10.3390/ijms25052770 - 27 Feb 2024
Cited by 2 | Viewed by 2057
Abstract
p.Asn1303Lys (N1303K) is a common missense variant of the CFTR gene, causing cystic fibrosis (CF). In this study, we initially evaluated the influence of CFTR modulators on the restoration of N1303K-CFTR function using intestinal organoids derived from four CF patients expressing the [...] Read more.
p.Asn1303Lys (N1303K) is a common missense variant of the CFTR gene, causing cystic fibrosis (CF). In this study, we initially evaluated the influence of CFTR modulators on the restoration of N1303K-CFTR function using intestinal organoids derived from four CF patients expressing the N1303K variant. The forskolin-induced swelling assay in organoids offered valuable insights about the beneficial effects of VX-770 + VX-661 + VX-445 (Elexacaftor + Tezacaftor + Ivacaftor, ETI) on N1303K-CFTR function restoration and about discouraging the prescription of VX-770 + VX-809 (Ivacaftor + Lumacaftor) or VX-770 + VX-661 (Ivacaftor + Tezacaftor) therapy for N1303K/class I patients. Then, a comprehensive assessment was conducted on an example of one patient with the N1303K/class I genotype to examine the ETI effect on the restoration of N1303K-CFTR function using in vitro the patient’s intestinal organoids, ex vivo the intestinal current measurements (ICM) method and assessment of the clinical status before and after targeted therapy. All obtained results are consistent with each other and have proven the effectiveness of ETI for the N1303K variant. ETI produced a significant positive effect on forskolin-induced swelling in N1303K/class I organoids indicating functional improvement of the CFTR protein; ICM demonstrated that ETI therapy restored CFTR function in the intestinal epithelium after three months of treatment, and the patient improved his clinical status and lung function, increased his body mass index (BMI) and reduced the lung pathogenic flora diversity, surprisingly without improving the sweat test results. Full article
(This article belongs to the Special Issue Research Advances on Cystic Fibrosis and CFTR Protein)
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17 pages, 13171 KiB  
Article
Elexacaftor Mediates the Rescue of F508del CFTR Functional Expression Interacting with MSD2
by Roberta Bongiorno, Alessandra Ludovico, Oscar Moran and Debora Baroni
Int. J. Mol. Sci. 2023, 24(16), 12838; https://doi.org/10.3390/ijms241612838 - 16 Aug 2023
Cited by 4 | Viewed by 1638
Abstract
Cystic fibrosis (CF) is one of the most frequent lethal autosomal recessive diseases affecting the Caucasian population. It is caused by loss of function variants of the cystic fibrosis transmembrane conductance regulator (CFTR), a membrane protein located on the apical side of epithelial [...] Read more.
Cystic fibrosis (CF) is one of the most frequent lethal autosomal recessive diseases affecting the Caucasian population. It is caused by loss of function variants of the cystic fibrosis transmembrane conductance regulator (CFTR), a membrane protein located on the apical side of epithelial cells. The most prevalent CF-causing mutation, the deletion of phenylalanine at position 508 (F508del), is characterized by folding and trafficking defects, resulting in the decreased functional expression of the protein on the plasma membrane. Two classes of small-molecule modulators, termed potentiators and correctors, respectively, have been developed to rescue either the gating or the cellular processing of defective F508del CFTR. Kaftrio, a next-generation triple-combination drug, consisting of the potentiator ivacaftor (VX770) and the two correctors tezacaftor (VX661) and elexacaftor (VX445), has been demonstrated to be a life-changing therapeutic modality for the majority of people with CF worldwide. While the mechanism of action of VX770 and VX661 is almost known, the precise mechanism of action and binding site of VX445 have not been conclusively determined. We investigated the activity of VX445 on mutant F508del to identify the protein domains whose expression is mostly affected by this corrector and to disclose its mechanisms of action. Our biochemical analyses revealed that VX445 specifically improves the expression and the maturation of MSD2, heterologously expressed in HEK 293 cells, and confirmed that its effect on the functional expression of defective F508del CFTR is additive either with type I or type II CFTR correctors. We are confident that our study will help to make a step forward in the comprehension of the etiopathology of the CF disease, as well as to give new information for the development and testing of combinations of even more effective correctors able to target mutation-specific defects of the CFTR protein. Full article
(This article belongs to the Special Issue Research Advances on Cystic Fibrosis and CFTR Protein)
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