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Cystic Fibrosis: Molecular Pathogenesis, Diagnosis, and Treatment
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Cystic Fibrosis: Molecular Pathogenesis, Diagnosis, and Treatment

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: 20 March 2025 | Viewed by 7190

Special Issue Editor

Dr. Valeria Rachela Villella

E-Mail Website
Guest Editor
1. Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, 80131 Napoli, Italy
2. CEINGE-Biotecnologie Avanzate Franco Salvatore, Via G. Salvatore, 486, 80145 Napoli, Italy
Interests: cystic fibrosis

Special Issue Information

Dear Colleagues,

Cystic Fibrosis (CF) is a rare disease caused by mutation of the gene encoding the CFTR protein. More than 2000 different mutations affecting it are known, the consequence of which always corresponds to an alteration/absence in the function of the CFTR. The quality of life of patients is greatly impaired, and although current therapies have significantly improved the lives of many patients with CF, still today, not all mutations are covered by effective treatment, making research the only way to reach a solution for everyone.

To date, the molecular mechanisms underlying this malfunction are not yet fully known, and although much progress has been made, many unknowns remain unaddressed. Several cellular mechanisms are altered in CF, each with a distinct effect on CFTR (dys)function, and many of the molecular pathways involved remain to be explored. The processing, trafficking and interactions of the CFTR protein represent an intrigued network of activities whose equilibrium, underlying its function, is finely ruled. This activates mechanisms that are still the subject of multiple studies on the effect of CFTR dysfunction.

The current modulators, which represent an excellent starting point for the resolution of the CFTR enigma, have a molecular and pathophysiological mechanism that is still open to functional hypotheses, and much research is still needed to arrive at a clear and precise answer.

The scope of this Special Issue focuses on, but is not limited to:

  • Molecular mechanisms and pathways of CFTR;
  • Molecular and protein interactions of CFTR;
  • Processing and trafficking of CFTR and involved proteins;
  • Molecular and functional studies on CFTR modulators;
  • New molecules and treatments;
  • Theratyping;
  • Pathogenesis of CF;
  • Alteration of cellular processes in cells and patients.

Dr. Valeria Rachela Villella
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

  • CFTR protein interactions
  • molecular mechanism and processing
  • modulators
  • new drugs
  • pathogenesis and theratyping

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Published Papers (4 papers)

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Research

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12 pages, 2934 KiB  
Article
Effect of CFTR Modulators on Oxidative Stress and Autophagy in Non-CFTR-Expressing Cells
by Filippo Scialò, Gustavo Cernera, Lorenza Polise, Giuseppe Castaldo, Felice Amato and Valeria Rachela Villella
Int. J. Mol. Sci. 2024, 25(19), 10360; https://doi.org/10.3390/ijms251910360 - 26 Sep 2024
Viewed by 743
Abstract
The triple combination therapy for cystic fibrosis (CF), including elexacaftor, tezacaftor and ivacaftor (ETI or Trikafta), has been shown to improve lung function and reduce pulmonary exacerbations, thereby enhancing the quality of life for most CF patients. Recent findings suggest that both the [...] Read more.
The triple combination therapy for cystic fibrosis (CF), including elexacaftor, tezacaftor and ivacaftor (ETI or Trikafta), has been shown to improve lung function and reduce pulmonary exacerbations, thereby enhancing the quality of life for most CF patients. Recent findings suggest that both the individual components and ETI may have potential off-target effects, highlighting the need to understand how these modulators impact cellular physiology, particularly in cells that do not express CF transmembrane conductance regulator (CFTR). We used HEK293 cells, as a cell model not expressing the CFTR protein, to evaluate the effect of ETI and each of its components on autophagic machinery and on the Rab5/7 components of the Rab pathway. We firstly demonstrate that the single modulators Teza and Iva, and the combinations ET and ETI, increased ROS production in the absence of their target while decreasing it in cells expressing the CFTR ∆F508del. This increase in cellular stress was followed by an increase in the total level of polyubiquitinated proteins as well as the p62 level and LC3II/LC3I ratio. Furthermore, we found that ETI had the opposite effect on Rabs by increasing Rab5 levels while decreasing Rab7. Interestingly, these changes were abolished by the expression of mutated CFTR. Overall, our data suggest that in the absence of their target, both the individual modulators and ETI increased ROS production and halted both autophagic flux and plasma membrane protein recycling. Full article
(This article belongs to the Special Issue Cystic Fibrosis: Molecular Pathogenesis, Diagnosis, and Treatment)
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19 pages, 2292 KiB  
Article
Insights into the Adolescent Cystic Fibrosis Airway Microbiome Using Shotgun Metagenomics
by Gillian McDermott, Aaron Walsh, Fiona Crispie, Susanna Frost, Peter Greally, Paul D. Cotter, Orla O’Sullivan and Julie Renwick
Int. J. Mol. Sci. 2024, 25(7), 3893; https://doi.org/10.3390/ijms25073893 - 31 Mar 2024
Cited by 1 | Viewed by 1465
Abstract
Cystic fibrosis (CF) is an inherited genetic disorder which manifests primarily in airway disease. Recent advances in molecular technologies have unearthed the diverse polymicrobial nature of the CF airway. Numerous studies have characterised the genus-level composition of this airway community using targeted 16S [...] Read more.
Cystic fibrosis (CF) is an inherited genetic disorder which manifests primarily in airway disease. Recent advances in molecular technologies have unearthed the diverse polymicrobial nature of the CF airway. Numerous studies have characterised the genus-level composition of this airway community using targeted 16S rDNA sequencing. Here, we employed whole-genome shotgun metagenomics to provide a more comprehensive understanding of the early CF airway microbiome. We collected 48 sputum samples from 11 adolescents and children with CF over a 12-month period and performed shotgun metagenomics on the Illumina NextSeq platform. We carried out functional and taxonomic analysis of the lung microbiome at the species and strain levels. Correlations between microbial diversity measures and independent demographic and clinical variables were performed. Shotgun metagenomics detected a greater diversity of bacteria than culture-based methods. A large proportion of the top 25 most-dominant species were anaerobes. Samples dominated by Staphylococcus aureus and Prevotella melaninogenica had significantly higher microbiome diversity, while no CF pathogen was associated with reduced microbial diversity. There was a diverse resistome present in all samples in this study, with 57.8% agreement between shotgun metagenomics and culture-based methods for detection of resistance. Pathogenic sequence types (STs) of S. aureus, Pseudomonas aeruginosa, Haemophilus influenzae and Stenotrophomonas maltophilia were observed to persist in young CF patients, while STs of S. aureus were both persistent and shared between patients. This study provides new insight into the temporal changes in strain level composition of the microbiome and the landscape of the resistome in young people with CF. Shotgun metagenomics could provide a very useful one-stop assay for detecting pathogens, emergence of resistance and conversion to persistent colonisation in early CF disease. Full article
(This article belongs to the Special Issue Cystic Fibrosis: Molecular Pathogenesis, Diagnosis, and Treatment)
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Review

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20 pages, 909 KiB  
Review
Cystic Fibrosis: A Journey through Time and Hope
by Pascal Trouvé, Aude Saint Pierre and Claude Férec
Int. J. Mol. Sci. 2024, 25(17), 9599; https://doi.org/10.3390/ijms25179599 - 4 Sep 2024
Viewed by 2293
Abstract
Just over thirty years is the span of a generation. It is also the time that has passed since the discovery of the gene responsible for cystic fibrosis. Today, it is safe to say that this discovery has revolutionized our understanding, research perspectives, [...] Read more.
Just over thirty years is the span of a generation. It is also the time that has passed since the discovery of the gene responsible for cystic fibrosis. Today, it is safe to say that this discovery has revolutionized our understanding, research perspectives, and management of this disease, which was, thirty years ago, a pediatric condition with a grim prognosis. The aim of this review is to present the advances that science and medicine have brought to our understanding of the pathophysiology of the disease and its management, which in many ways, epitomizes modern molecular genetic research. Since the discovery of the cystic fibrosis transmembrane conductance regulator (CFTR) gene in 1989, modeling the CFTR protein, deciphering its function as an ion channel, and identifying its molecular partners have led to numerous therapeutic advances. The most significant advancement in this field has been the discovery of protein modulators that can target its membrane localization and chloride channel activity. However, further progress is needed to ensure that all patients can benefit from a therapy tailored to their mutations, with the primary challenge being the development of treatments for mutations leading to a complete absence of the protein. The present review delves into the history of the multifaceted world of CF, covering main historical facts, current landscape, clinical management, emerging therapies, patient perspectives, and the importance of ongoing research, bridging science and medicine in the fight against the disease. Full article
(This article belongs to the Special Issue Cystic Fibrosis: Molecular Pathogenesis, Diagnosis, and Treatment)
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16 pages, 528 KiB  
Review
The Effect of Complex Alleles of the CFTR Gene on the Clinical Manifestations of Cystic Fibrosis and the Effectiveness of Targeted Therapy
by Maria Krasnova, Anna Efremova, Artem Bukhonin, Elena Zhekaite, Tatiana Bukharova, Yuliya Melyanovskaya, Dmitry Goldshtein and Elena Kondratyeva
Int. J. Mol. Sci. 2024, 25(1), 114; https://doi.org/10.3390/ijms25010114 - 21 Dec 2023
Cited by 3 | Viewed by 2189
Abstract
The authors of this article analyzed the available literature with the results of studying the prevalence of complex alleles of the CFTR gene among patients with cystic fibrosis, and their pathogenicity and influence on targeted therapy with CFTR modulators. Cystic fibrosis (CF) is [...] Read more.
The authors of this article analyzed the available literature with the results of studying the prevalence of complex alleles of the CFTR gene among patients with cystic fibrosis, and their pathogenicity and influence on targeted therapy with CFTR modulators. Cystic fibrosis (CF) is a multisystemic autosomal recessive disease caused by a defect in the expression of the CFTR protein, and more than 2000 genetic variants are known. Clinically significant variants are divided into seven classes. Information about the frequency of complex alleles appears in a number of registers, along with the traditional presentation of data on genetic variants. Complex alleles (those with the presence of more than two nucleotide variants on one allele) can complicate the diagnosis of the disease, and change the clinical manifestations of cystic fibrosis and the response to treatment, since each variant in the complex allele can contribute to the functional activity of the CFTR protein, changing it both in terms of increasing and decreasing function. The role of complex alleles is often underestimated, and their frequency has not been studied. At the moment, characteristic frequently encountered complex alleles have been found for several populations of patients with cystic fibrosis, but the prevalence and pathogenicity of newly detected complex alleles require additional research. In this review, more than 35 complex alleles of the CFTR gene from existing research studies were analyzed, and an analysis of their influence on the manifestations of the disease and the effectiveness of CFTR modulators was also described. Full article
(This article belongs to the Special Issue Cystic Fibrosis: Molecular Pathogenesis, Diagnosis, and Treatment)
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