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Cystic Fibrosis: Diagnosis, Treatment, and Related Disorders
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Cystic Fibrosis: Diagnosis, Treatment, and Related Disorders

A special issue of Journal of Personalized Medicine (ISSN 2075-4426). This special issue belongs to the section "Pharmacogenetics".

Deadline for manuscript submissions: closed (10 August 2023) | Viewed by 12284

Special Issue Editors

Dr. Miquéias Lopes-Pacheco

E-Mail Website
Guest Editor
Biosystems & Integrative Sciences Institute (BioISI), Faculty of Sciences, University of Lisbon, 1749-016 Lisbon, Portugal
Interests: cell therapy; CFTR modulators; drug development; intracellular trafficking; precision medicine; protein folding; proteostasis; rare mutations; respiratory disease
Dr. Neeraj Sharma

E-Mail Website
Guest Editor
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
Interests: airway disease; cell models; CFTR-related disorders; modifier genes; nonsense mutations; precision medicine; RNA splicing; sweat chloride measurements
Dr. Shafagh Waters

E-Mail Website
Guest Editor
School of Women’s and Children’s Health, Faculty of Medicine, University of New South Wales, Sydney, NSW 2052, Australia
Interests: airway disease; cell models; CFTR modulators; CF-related comorbidites; extracellular vesicles; intracellular trafficking; personalized medicine; protein folding; rare mutations

Special Issue Information

Dear Colleagues,

Over the last decade, major clinical advances have been achieved in delaying cystic fibrosis (CF) progress with the implementation of newborn screening programs and development of novel therapies, including CFTR modulator drugs.

CF-causing mutations can promote pleiotropic defects on the CF transmembrane conductance regulator (CFTR) protein, thus affecting its expression, trafficking, function, stability, or a combination thereof. Accordingly, a combination of CFTR modulator drugs is needed to most disease-associated CFTR variants in order to repair trafficking and functional defects at therapeutically relevant levels. Nevertheless, not all CF-causing mutations are responsive to the clinically available CFTR modulator drugs. Development of CFTR-directed therapies should also aim for rare mutations identified in a minority non-Caucasian population. Furthermore, a number of modifier genes and epigenetic factors have been associated with the individual responsiveness of these new drugs and with the potential development of comorbidities with disease progression. Assessment of CFTR function and response to modulator drugs in CF carriers who present with CFTR-related disorders is warranted.

Many novel assays and models have emerged to better understand the genotype–phenotype relationship and to predict drug effectiveness in a personalized medicine approach. In parallel, mutation-agnostic therapies (i.e., independent of CFTR mutation) are under development. These include cell-based and gene-based therapies, ENaC inhibitors, modulators of alternative chloride channels, small artificial transmembrane anion transporters (anionophores), as well as symptomatic therapies, such as novel anti-inflammatory drugs, antibiotics, and mucolytics.

This Special Issue on “Cystic Fibrosis” aims to gather a collection of reviews and original articles focused on “Diagnosis, Treatment, and Related Disorders” to this disease at basic, translational, and clinical levels to provide expert insights and perspectives on advances in the field.

Dr. Miquéias Lopes-Pacheco
Dr. Neeraj Sharma
Dr. Shafagh Waters
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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. Journal of Personalized Medicine is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 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

  • CFTR modulators
  • CFTR trafficking
  • proteostasis
  • modifier genes
  • epigenetic factors
  • airway epithelium
  • cell models
  • alternative channels
  • gene therapy
  • cell therapy

Published Papers (4 papers)

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Research

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11 pages, 818 KiB  
Article
Factors Predisposing the Response to Lumacaftor/Ivacaftor in People with Cystic Fibrosis
by Julie Mésinèle, Manon Ruffin, Loïc Guillot, Pierre-Yves Boëlle, Harriet Corvol and on behalf of the French CF Modifier Gene Study Investigators
J. Pers. Med. 2022, 12(2), 252; https://doi.org/10.3390/jpm12020252 - 10 Feb 2022
Cited by 3 | Viewed by 1766
Abstract
Lumacaftor/ivacaftor (LUMA-IVA) therapy is prescribed to people with cystic fibrosis (pwCF) homozygous for the Phe508del-CFTR variant to restore CFTR protein function. There is, however, large inter-individual variability in treatment response. Here, we seek to identify clinical and/or genetic factors that may modulate [...] Read more.
Lumacaftor/ivacaftor (LUMA-IVA) therapy is prescribed to people with cystic fibrosis (pwCF) homozygous for the Phe508del-CFTR variant to restore CFTR protein function. There is, however, large inter-individual variability in treatment response. Here, we seek to identify clinical and/or genetic factors that may modulate the response to this CFTR modulator therapy. A total of 765 pwCF older than 12 years under LUMA-IVA therapy and with lung function and nutritional measurements available before and after treatment initiation were included. Response to treatment was determined by the change in lung function and nutritional status, from baseline and over the first two years after initiation, and it was assessed by weighted generalized estimating equation models. Gains in lung function and nutritional status were observed after 6 months of treatment (on average 2.11 ± 7.81% for percent predicted FEV1 and 0.44 ± 0.77 kg/m2 for BMI) and sustained over the 2 years. We observed that the more severe patients gained the most in lung function and nutritional status. While females started with a nutritional status more impaired than males, they had a larger response and regained BMI Z-score values similar to men after 2 years of treatment. We observed no association between variants in solute carrier (SLC) genes and the respiratory function response to LUMA-IVA, but the SLC6A14 rs12839137 variant was associated with the nutritional response. Further investigations, including other genomic regions, will be needed to fully explore the inter-individual variability of the response to LUMA-IVA. Full article
(This article belongs to the Special Issue Cystic Fibrosis: Diagnosis, Treatment, and Related Disorders)
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Review

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23 pages, 1233 KiB  
Review
Advances in Preclinical In Vitro Models for the Translation of Precision Medicine for Cystic Fibrosis
by Iris A. L. Silva, Onofrio Laselva and Miquéias Lopes-Pacheco
J. Pers. Med. 2022, 12(8), 1321; https://doi.org/10.3390/jpm12081321 - 16 Aug 2022
Cited by 14 | Viewed by 5093
Abstract
The development of preclinical in vitro models has provided significant progress to the studies of cystic fibrosis (CF), a frequently fatal monogenic disease caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR) protein. Numerous cell lines were generated over [...] Read more.
The development of preclinical in vitro models has provided significant progress to the studies of cystic fibrosis (CF), a frequently fatal monogenic disease caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR) protein. Numerous cell lines were generated over the last 30 years and they have been instrumental not only in enhancing the understanding of CF pathological mechanisms but also in developing therapies targeting the underlying defects in CFTR mutations with further validation in patient-derived samples. Furthermore, recent advances toward precision medicine in CF have been made possible by optimizing protocols and establishing novel assays using human bronchial, nasal and rectal tissues, and by progressing from two-dimensional monocultures to more complex three-dimensional culture platforms. These models also enable to potentially predict clinical efficacy and responsiveness to CFTR modulator therapies at an individual level. In parallel, advanced systems, such as induced pluripotent stem cells and organ-on-a-chip, continue to be developed in order to more closely recapitulate human physiology for disease modeling and drug testing. In this review, we have highlighted novel and optimized cell models that are being used in CF research to develop novel CFTR-directed therapies (or alternative therapeutic interventions) and to expand the usage of existing modulator drugs to common and rare CF-causing mutations. Full article
(This article belongs to the Special Issue Cystic Fibrosis: Diagnosis, Treatment, and Related Disorders)
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22 pages, 1899 KiB  
Review
CFTR and Gastrointestinal Cancers: An Update
by Rahul Bhattacharya, Zachary Blankenheim, Patricia M. Scott and Robert T. Cormier
J. Pers. Med. 2022, 12(6), 868; https://doi.org/10.3390/jpm12060868 - 25 May 2022
Cited by 8 | Viewed by 3143
Abstract
Cystic Fibrosis (CF) is a disease caused by mutations in the CFTR gene that severely affects the lungs as well as extra-pulmonary tissues, including the gastrointestinal (GI) tract. CFTR dysfunction resulting from either mutations or the downregulation of its expression has been shown [...] Read more.
Cystic Fibrosis (CF) is a disease caused by mutations in the CFTR gene that severely affects the lungs as well as extra-pulmonary tissues, including the gastrointestinal (GI) tract. CFTR dysfunction resulting from either mutations or the downregulation of its expression has been shown to promote carcinogenesis. An example is the enhanced risk for several types of cancer in patients with CF, especially cancers of the GI tract. CFTR also acts as a tumor suppressor in diverse sporadic epithelial cancers in many tissues, primarily due to the silencing of CFTR expression via multiple mechanisms, but especially due to epigenetic regulation. This review provides an update on the latest research linking CFTR-deficiency to GI cancers, in both CF patients and in sporadic GI cancers, with a particular focus on cancer of the intestinal tract. It will discuss changes in the tissue landscape linked to CFTR-deficiency that may promote cancer development such as breakdowns in physical barriers, microbial dysbiosis and inflammation. It will also discuss molecular pathways and mechanisms that act upstream to modulate CFTR expression, such as by epigenetic silencing, as well as molecular pathways that act downstream of CFTR-deficiency, such as the dysregulation of the Wnt/β-catenin and NF-κB signaling pathways. Finally, it will discuss the emerging CFTR modulator drugs that have shown promising results in improving CFTR function in CF patients. The potential impact of these modulator drugs on the treatment and prevention of GI cancers can provide a new example of personalized cancer medicine. Full article
(This article belongs to the Special Issue Cystic Fibrosis: Diagnosis, Treatment, and Related Disorders)
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Other

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4 pages, 222 KiB  
Commentary
Advances in Cystic Fibrosis Research in Qatar: A Commentary
by Samer Hammoudeh and Ibrahim A. Janahi
J. Pers. Med. 2023, 13(3), 448; https://doi.org/10.3390/jpm13030448 - 28 Feb 2023
Viewed by 872
Abstract
Cystic fibrosis is a genetic disorder caused by a Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene defect. Many across the globe suffer the debilitating symptoms. The aim of this commentary is to briefly cover various aspects related to the disease in the Arab [...] Read more.
Cystic fibrosis is a genetic disorder caused by a Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene defect. Many across the globe suffer the debilitating symptoms. The aim of this commentary is to briefly cover various aspects related to the disease in the Arab world and then in Qatar. Full article
(This article belongs to the Special Issue Cystic Fibrosis: Diagnosis, Treatment, and Related Disorders)
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