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Cystic Fibrosis: Genetics, Pathophysiology and Novel Therapeutic Approaches
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Cystic Fibrosis: Genetics, Pathophysiology and Novel Therapeutic Approaches

A special issue of Journal of Respiration (ISSN 2673-527X).

Deadline for manuscript submissions: closed (30 June 2022) | Viewed by 16337

Special Issue Editors

Dr. Massimo Conese

E-Mail Website
Guest Editor
Department of Clinical and Experimental Medicine, University of Foggia, 71122 Foggia, Italy
Interests: nose-to-brain delivery; applications of nanoparticles to drug delivery; Parkinson’s disease; mucopenetration; mesenchymal stem cells; exosomes; airway diseases
Special Issues, Collections and Topics in MDPI journals
Dr. Onofrio Laselva

E-Mail Website
Guest Editor
Laboratory of Experimental and Regenerative Medicine, Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy
Interests: CFTR protein; CF genetics; personalized medicine; infection and inflammation
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cystic fibrosis (CF) is a life-threatening autosomal recessive disorder due to mutations in the CF Transmembrane Conductance Regulator (CFTR) gene that cause morbidity and mortality mainly by inducing lung disease. This Special Issue is devoted to appraising the most recent developments in CF research and its clinical facets, focusing on the fields of genetics, theranostics, immunology, infections, inflammation, and novel therapeutic approaches. It will present genotype/phenotype correlations, rare mutations, and modifier genes of CF lung disease—one of the most interesting genetic aspects under intense study. Established pathophysiologic hallmarks of CF lung disease are opportunistic bacterial infections and heightened inflammatory response. Research is now focused on both the involvement of other ion channel/transporters and the host innate and adaptive immune response. In the coronavirus 2019 (COVID-19) era, the natural history of CF pathophysiology is changing, thereby this Special Issue will be insightful in discussing how the present pandemic infection could determine other clinical features in CF patients. Finally, basic and applied research have sought and identified etiological treatments for CF, highlighted by the clinical use of modulators (potentiators, correctors) of the mutated CFTR protein. Novel genetic and stem cell-based treatments as potential therapeutic approaches to cure CF are at the forefront of CF research and will be also covered in this Special Issue.

Prof. Dr. Massimo Conese
Dr. Onofrio Laselva
Guest Editors

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1000 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • cystic fibrosis
  • CFTR genotype
  • modifier genes
  • COVID-19
  • ion channels/transporters
  • immune cells
  • extracellular vesicles
  • CFTR modulators
  • gene editing
  • stem cells

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Published Papers (3 papers)

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Research

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12 pages, 3813 KiB  
Article
Differential Effects of Oleuropein and Hydroxytyrosol on Aggregation and Stability of CFTR NBD1-ΔF508 Domain
by Christopher S. Robinson, Jennifer A. Wyderko, Yeng Vang, Galen Martin and Robert T. Youker
J. Respir. 2021, 1(3), 204-215; https://doi.org/10.3390/jor1030019 - 4 Aug 2021
Viewed by 3348
Abstract
Cystic Fibrosis (CF) is caused by loss of function mutations in the Cystic Fibrosis transmembrane conductance regulator (CFTR). The folding and assembly of CFTR is inefficient. Deletion of F508 in the first nucleotide binding domain (NBD1-ΔF508) further disrupts protein stability leading to endoplasmic [...] Read more.
Cystic Fibrosis (CF) is caused by loss of function mutations in the Cystic Fibrosis transmembrane conductance regulator (CFTR). The folding and assembly of CFTR is inefficient. Deletion of F508 in the first nucleotide binding domain (NBD1-ΔF508) further disrupts protein stability leading to endoplasmic reticulum retention and proteasomal degradation. Stabilization and prevention of NBD1-ΔF508 aggregation is critical to rescuing the folding and function of the entire CFTR channel. We report that the phenolic compounds Oleuropein and Hydroxytryosol reduce aggregation of NBD1-ΔF508. The NBD1-ΔF508 aggregate size was smaller in the presence of Hydroxytryosol as determined by dynamic light scattering. Neither phenolic compound increased the thermal stability of NBD1-ΔF508 as measured by differential scanning fluorimetry. Interestingly, Hydroxytyrosol inhibited the stabilizing effect of the indole compound BIA, a known stabilizer, on NBD1-ΔF508. Molecular docking studies predicted that Oleuropein preferred to bind in the F1-type core ATP-binding subdomain in NBD1. In contrast, Hydroxytyrosol preferred to bind in the α4/α5/α6 helical bundle of the ABCα subdomain of NBD1 next to the putative binding site for BIA. This result suggests that Hydroxytyrosol interferes with BIA binding, thus providing an explanation for the antagonistic effect on NBD1 stability upon incubation with both compounds. To our knowledge, these studies are the first to explore the effects of these two phenolic compounds on the aggregation and stability of NBD1-ΔF508 domain of CFTR. Full article
(This article belongs to the Special Issue Cystic Fibrosis: Genetics, Pathophysiology and Novel Therapeutic Approaches)
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Review

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18 pages, 326 KiB  
Review
CFTR Modulator Therapy for Rare CFTR Mutants
by Marco Mergiotti, Alessandra Murabito, Giulia Prono and Alessandra Ghigo
J. Respir. 2022, 2(2), 59-76; https://doi.org/10.3390/jor2020005 - 5 Apr 2022
Cited by 7 | Viewed by 5866
Abstract
Cystic fibrosis (CF), the most common genetic disease among the Caucasian population, is caused by mutations in the gene encoding for the CF transmembrane conductance regulator (CFTR), a chloride epithelial channel whose dysfunction results in severe airway obstruction and inflammation, eventually leading to [...] Read more.
Cystic fibrosis (CF), the most common genetic disease among the Caucasian population, is caused by mutations in the gene encoding for the CF transmembrane conductance regulator (CFTR), a chloride epithelial channel whose dysfunction results in severe airway obstruction and inflammation, eventually leading to respiratory failure. The discovery of the CFTR gene in 1989 provided new insights into the basic genetic defect of CF and allowed the study of potential therapies targeting the aberrant protein. In recent years, the approval of “CFTR modulators”, the first molecules designed to selectively target the underlying molecular defects caused by specific CF-causing mutations, marked the beginning of a new era in CF treatment. These drugs have been demonstrated to significantly improve lung function and ameliorate the quality of life of many patients, especially those bearing the most common CFTR mutatant F508del. However, a substantial portion of CF subjects, accounting for ~20% of the European CF population, carry rare CFTR mutations and are still not eligible for CFTR modulator therapy, partly due to our limited understanding of the molecular defects associated with these genetic alterations. Thus, the implementation of models to study the phenotype of these rare CFTR mutations and their response to currently approved drugs, as well as to compounds under research and clinical development, is of key importance. The purpose of this review is to summarize the current knowledge on the potential of CFTR modulators in rescuing the function of rare CF-causing CFTR variants, focusing on both investigational and clinically approved molecules. Full article
(This article belongs to the Special Issue Cystic Fibrosis: Genetics, Pathophysiology and Novel Therapeutic Approaches)
19 pages, 640 KiB  
Review
Three-Dimensional Airway Spheroids and Organoids for Cystic Fibrosis Research
by Onofrio Laselva and Massimo Conese
J. Respir. 2021, 1(4), 229-247; https://doi.org/10.3390/jor1040022 - 7 Oct 2021
Cited by 3 | Viewed by 5331
Abstract
Cystic fibrosis (CF) is an autosomal recessive multi-organ disease caused by mutations in the CF Transmembrane Conductance Regulator (CFTR) gene, with morbidity and mortality primacy related to the lung disease. The CFTR protein, a chloride/bicarbonate channel, is expressed at the apical [...] Read more.
Cystic fibrosis (CF) is an autosomal recessive multi-organ disease caused by mutations in the CF Transmembrane Conductance Regulator (CFTR) gene, with morbidity and mortality primacy related to the lung disease. The CFTR protein, a chloride/bicarbonate channel, is expressed at the apical side of airway epithelial cells and is mainly involved in appropriate ion and fluid transport across the epithelium. Although many animal and cellular models have been developed to study the pathophysiological consequences of the lack/dysfunction of CFTR, only the three-dimensional (3D) structures termed “spheroids” and “organoids” can enable the reconstruction of airway mucosa to model organ development, disease pathophysiology, and drug screening. Airway spheroids and organoids can be derived from different sources, including adult lungs and induced pluripotent stem cells (iPSCs), each with its advantages and limits. Here, we review the major features of airway spheroids and organoids, anticipating that their potential in the CF field has not been fully shown. Further work is mandatory to understand whether they can accomplish better outcomes than other culture conditions of airway epithelial cells for CF personalized therapies and tissue engineering aims. Full article
(This article belongs to the Special Issue Cystic Fibrosis: Genetics, Pathophysiology and Novel Therapeutic Approaches)
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