Cystic Fibrosis: Therapy and Genetics

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Human Genomics and Genetic Diseases".

Deadline for manuscript submissions: closed (4 February 2019) | Viewed by 70335

Special Issue Editors

Hospital for Sick Children University of Toronto, Department of Pathology and Laboratory Medicine, Toronto, ON M5S 1A8, Canada
Interests: cystic fibrosis
Department of Gene Therapy, National Heart and Lung Institute, London SW3 6LY, UK
Interests: gene therapy; cystic fibrosis; biomarker development
University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
Interests: gene therapy; cystic fibrosis; airway surface liquid; bronchiectasis

Special Issue Information

Dear Colleagues,

Cystic fibrosis (CF) is the most common monogenic fatal disorder in the Caucasian population caused by recessive mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). The disease affects multiple organs including the lung, pancreas, intestine, gall bladder and reproductive organs, however, lung failure due to chronic infection and inflammation is responsible for the most current CF-related morbidity and mortality. Based on the patient lifespan improvement over time, cystic fibrosis research is an excellent example that research brings clinical benefits to patients. CF is a complex disease, but with research in different fields such as nutrition, genetics and airway infection, this has led to various treatments including pancreatic enzyme replacement therapy and infection control to help patients to cope with disease symptoms. CFTR protein is a cyclic AMP-dependent ion channel and mutations that affect its function or dramatically reduce its expression level has led to defects in ion transport in multiple epithelial organs such as lung, pancreas, and intestine. Recent efforts in developing drugs for CFTR-targeting has provided proof that the concept of treating the cause of the disease is a better strategy. For example, the new drug, Ivacaftor, is shown to be efficacious for a small portion of CF patients. Ivacaftor can activate a mutant CFTR channel (such as the one with G551D mutation) and enhance the activity of a normal CFTR channel. In combination with another drug, lumacaftor, which can enhance protein trafficking to make more mutant CFTR protein to reach the cell membrane, Ivacaftor can provide some benefits to a significant portion of CF patients. Although these new drug developments have reached a milestone in treating the disease, more effective treatments are needed for all patients. In addition, for those patients whose mutations cause no CFTR protein expression, these new drugs will not work for them. Therefore, more research is needed to develop better or more effective treatments. Gene therapy has long been sought as a novel approach to directly treat CF lung disease. Despite the dismal outcomes in the past, the approach deserves a new look in this post genomic research era for the following reasons. First, the past efforts, although not successful, did help to understand the major barriers to the approach, such as safe and efficient gene delivery, and sustained therapeutic gene expression. These studies have also allowed the development of methods for assessing therapeutic effects in vivo. Second, progress has been made to overcome these challenges, such as new delivery vectors and methods. Third, there are better cell and animal disease models for testing CF gene therapy. Furthermore, the recent advancements in engineering site-specific endonucleases will allow the development of permanent gene correction strategies to overcome the problem of sustained therapeutic gene expression. Finally, the benefit of this approach is too big to ignore. Since CF gene therapy is used to target the cause of the CF lung disease, the approach is expected to be effective if a significant protein or target cells can be corrected. In addition, CF gene therapy, if successful, will reduce the drug burden and improve the life quality for patients. CF patients with the same mutation show different disease severity indicating that genetic background influences disease progression. Genetic studies have identified modifying genes which provide potential new targets for the development of CF therapies, including both drug and gene therapies. Therefore, the current issue of Genes is dedicated to publish articles describing state of the art research in field of CF genetics and therapeutic development. In this special issue, we are calling for papers, reviews and original research articles related to CF genetics, CFTR-targeting therapies, patients-based primary cell models, CF animal models, genetic tools for CF gene therapy, and clinical assessments of CF therapeutics.

Prof. Jim Hu
Prof. Uta Griesenbach
Prof. Joseph Zabner
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. Genes 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

  • Cystic fibrosis
  • airway disease
  • primary airway epithelial cells
  • CF disease models
  • CFTR mutations
  • gene therapy
  • gene editing
  • gene therapy vectors

Published Papers (7 papers)

Order results
Result details
Select all
Export citation of selected articles as:

Research

Jump to: Review

17 pages, 3835 KiB  
Article
TALEN-Mediated Gene Targeting for Cystic Fibrosis-Gene Therapy
by Emily Xia, Yiqian Zhang, Huibi Cao, Jun Li, Rongqi Duan and Jim Hu
Genes 2019, 10(1), 39; https://0-doi-org.brum.beds.ac.uk/10.3390/genes10010039 - 11 Jan 2019
Cited by 24 | Viewed by 7954
Abstract
Cystic fibrosis (CF) is an inherited monogenic disorder, amenable to gene-based therapies. Because CF lung disease is currently the major cause of mortality and morbidity, and the lung airway is readily accessible to gene delivery, the major CF gene therapy effort at present [...] Read more.
Cystic fibrosis (CF) is an inherited monogenic disorder, amenable to gene-based therapies. Because CF lung disease is currently the major cause of mortality and morbidity, and the lung airway is readily accessible to gene delivery, the major CF gene therapy effort at present is directed to the lung. Although airway epithelial cells are renewed slowly, permanent gene correction through gene editing or targeting in airway stem cells is needed to perpetuate the therapeutic effect. Transcription activator-like effector nuclease (TALEN) has been utilized widely for a variety of gene editing applications. The stringent requirement for nuclease binding target sites allows for gene editing with precision. In this study, we engineered helper-dependent adenoviral (HD-Ad) vectors to deliver a pair of TALENs together with donor DNA targeting the human AAVS1 locus. With homology arms of 4 kb in length, we demonstrated precise insertion of either a LacZ reporter gene or a human cystic fibrosis transmembrane conductance regulator (CFTR) minigene (cDNA) into the target site. Using the LacZ reporter, we determined the efficiency of gene integration to be about 5%. In the CFTR vector transduced cells, we were able to detect CFTR mRNA expression using qPCR and function correction using fluorometric image plate reader (FLIPR) and iodide efflux assays. Taken together, these findings suggest a new direction for future in vitro and in vivo studies in CF gene editing. Full article
(This article belongs to the Special Issue Cystic Fibrosis: Therapy and Genetics)
Show Figures

Figure 1

Review

Jump to: Research

17 pages, 1693 KiB  
Review
Gene and Base Editing as a Therapeutic Option for Cystic Fibrosis—Learning from Other Diseases
by Karen Mention, Lúcia Santos and Patrick T. Harrison
Genes 2019, 10(5), 387; https://0-doi-org.brum.beds.ac.uk/10.3390/genes10050387 - 21 May 2019
Cited by 23 | Viewed by 8141
Abstract
Cystic fibrosis (CF) is a monogenic autosomal recessive disorder caused by mutations in the CFTR gene. There are at least 346 disease-causing variants in the CFTR gene, but effective small-molecule therapies exist for only ~10% of them. One option to treat all mutations [...] Read more.
Cystic fibrosis (CF) is a monogenic autosomal recessive disorder caused by mutations in the CFTR gene. There are at least 346 disease-causing variants in the CFTR gene, but effective small-molecule therapies exist for only ~10% of them. One option to treat all mutations is CFTR cDNA-based therapy, but clinical trials to date have only been able to stabilise rather than improve lung function disease in patients. While cDNA-based therapy is already a clinical reality for a number of diseases, some animal studies have clearly established that precision genome editing can be significantly more effective than cDNA addition. These observations have led to a number of gene-editing clinical trials for a small number of such genetic disorders. To date, gene-editing strategies to correct CFTR mutations have been conducted exclusively in cell models, with no in vivo gene-editing studies yet described. Here, we highlight some of the key breakthroughs in in vivo and ex vivo gene and base editing in animal models for other diseases and discuss what might be learned from these studies in the development of editing strategies that may be applied to cystic fibrosis as a potential therapeutic approach. There are many hurdles that need to be overcome, including the in vivo delivery of editing machinery or successful engraftment of ex vivo-edited cells, as well as minimising potential off-target effects. However, a successful proof-of-concept study for gene or base editing in one or more of the available CF animal models could pave the way towards a long-term therapeutic strategy for this disease. Full article
(This article belongs to the Special Issue Cystic Fibrosis: Therapy and Genetics)
Show Figures

Figure 1

11 pages, 641 KiB  
Review
Cell-Selective Regulation of CFTR Gene Expression: Relevance to Gene Editing Therapeutics
by Hannah Swahn and Ann Harris
Genes 2019, 10(3), 235; https://0-doi-org.brum.beds.ac.uk/10.3390/genes10030235 - 19 Mar 2019
Cited by 21 | Viewed by 6673
Abstract
The cystic fibrosis transmembrane conductance regulator (CFTR) gene is an attractive target for gene editing approaches, which may yield novel therapeutic approaches for genetic diseases such as cystic fibrosis (CF). However, for gene editing to be effective, aspects of the three-dimensional [...] Read more.
The cystic fibrosis transmembrane conductance regulator (CFTR) gene is an attractive target for gene editing approaches, which may yield novel therapeutic approaches for genetic diseases such as cystic fibrosis (CF). However, for gene editing to be effective, aspects of the three-dimensional (3D) structure and cis-regulatory elements governing the dynamic expression of CFTR need to be considered. In this review, we focus on the higher order chromatin organization required for normal CFTR locus function, together with the complex mechanisms controlling expression of the gene in different cell types impaired by CF pathology. Across all cells, the CFTR locus is organized into an invariant topologically associated domain (TAD) established by the architectural proteins CCCTC-binding factor (CTCF) and cohesin complex. Additional insulator elements within the TAD also recruit these factors. Although the CFTR promoter is required for basal levels of expression, cis-regulatory elements (CREs) in intergenic and intronic regions are crucial for cell-specific and temporal coordination of CFTR transcription. These CREs are recruited to the promoter through chromatin looping mechanisms and enhance cell-type-specific expression. These features of the CFTR locus should be considered when designing gene-editing approaches, since failure to recognize their importance may disrupt gene expression and reduce the efficacy of therapies. Full article
(This article belongs to the Special Issue Cystic Fibrosis: Therapy and Genetics)
Show Figures

Figure 1

17 pages, 327 KiB  
Review
Lentiviral Vectors for the Treatment and Prevention of Cystic Fibrosis Lung Disease
by Laura I. Marquez Loza, Eric C. Yuen and Paul B. McCray, Jr.
Genes 2019, 10(3), 218; https://0-doi-org.brum.beds.ac.uk/10.3390/genes10030218 - 14 Mar 2019
Cited by 44 | Viewed by 8836
Abstract
Despite the continued development of cystic fibrosis transmembrane conductance regulator (CFTR) modulator drugs for the treatment of cystic fibrosis (CF), the need for mutation agnostic treatments remains. In a sub-group of CF individuals with mutations that may not respond to modulators, such as [...] Read more.
Despite the continued development of cystic fibrosis transmembrane conductance regulator (CFTR) modulator drugs for the treatment of cystic fibrosis (CF), the need for mutation agnostic treatments remains. In a sub-group of CF individuals with mutations that may not respond to modulators, such as those with nonsense mutations, CFTR gene transfer to airway epithelia offers the potential for an effective treatment. Lentiviral vectors are well-suited for this purpose because they transduce nondividing cells, and provide long-term transgene expression. Studies in primary cultures of human CF airway epithelia and CF animal models demonstrate the long-term correction of CF phenotypes and low immunogenicity using lentiviral vectors. Further development of CF gene therapy requires the investigation of optimal CFTR expression in the airways. Lentiviral vectors with improved safety features have minimized insertional mutagenesis safety concerns raised in early clinical trials for severe combined immunodeficiency using γ-retroviral vectors. Recent clinical trials using improved lentiviral vectors support the feasibility and safety of lentiviral gene therapy for monogenetic diseases. While work remains to be done before CF gene therapy reaches the bedside, recent advances in lentiviral vector development reviewed here are encouraging and suggest it could be tested in clinical studies in the near future. Full article
(This article belongs to the Special Issue Cystic Fibrosis: Therapy and Genetics)
23 pages, 1393 KiB  
Review
Progression of Cystic Fibrosis Lung Disease from Childhood to Adulthood: Neutrophils, Neutrophil Extracellular Trap (NET) Formation, and NET Degradation
by Meraj A. Khan, Zubair Sabz Ali, Neil Sweezey, Hartmut Grasemann and Nades Palaniyar
Genes 2019, 10(3), 183; https://0-doi-org.brum.beds.ac.uk/10.3390/genes10030183 - 26 Feb 2019
Cited by 62 | Viewed by 7951
Abstract
Genetic defects in cystic fibrosis (CF) transmembrane conductance regulator (CFTR) gene cause CF. Infants with CFTR mutations show a peribronchial neutrophil infiltration prior to the establishment of infection in their lung. The inflammatory response progressively increases in children that include both upper and [...] Read more.
Genetic defects in cystic fibrosis (CF) transmembrane conductance regulator (CFTR) gene cause CF. Infants with CFTR mutations show a peribronchial neutrophil infiltration prior to the establishment of infection in their lung. The inflammatory response progressively increases in children that include both upper and lower airways. Infectious and inflammatory response leads to an increase in mucus viscosity and mucus plugging of small and medium-size bronchioles. Eventually, neutrophils chronically infiltrate the airways with biofilm or chronic bacterial infection. Perpetual infection and airway inflammation destroy the lungs, which leads to increased morbidity and eventual mortality in most of the patients with CF. Studies have now established that neutrophil cytotoxins, extracellular DNA, and neutrophil extracellular traps (NETs) are associated with increased mucus clogging and lung injury in CF. In addition to opportunistic pathogens, various aspects of the CF airway milieux (e.g., airway pH, salt concentration, and neutrophil phenotypes) influence the NETotic capacity of neutrophils. CF airway milieu may promote the survival of neutrophils and eventual pro-inflammatory aberrant NETosis, rather than the anti-inflammatory apoptotic death in these cells. Degrading NETs helps to manage CF airway disease; since DNAse treatment release cytotoxins from the NETs, further improvements are needed to degrade NETs with maximal positive effects. Neutrophil-T cell interactions may be important in regulating viral infection-mediated pulmonary exacerbations in patients with bacterial infections. Therefore, clarifying the role of neutrophils and NETs in CF lung disease and identifying therapies that preserve the positive effects of neutrophils, while reducing the detrimental effects of NETs and cytotoxic components, are essential in achieving innovative therapeutic advances. Full article
(This article belongs to the Special Issue Cystic Fibrosis: Therapy and Genetics)
Show Figures

Figure 1

15 pages, 490 KiB  
Review
Transcriptome Profiling and Molecular Therapeutic Advances in Cystic Fibrosis: Recent Insights
by Justin E. Ideozu, Xi Zhang, Susanna McColley and Hara Levy
Genes 2019, 10(3), 180; https://0-doi-org.brum.beds.ac.uk/10.3390/genes10030180 - 26 Feb 2019
Cited by 12 | Viewed by 5367
Abstract
In cystic fibrosis (CF), mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene disrupt the capacity of the encoded protein to function as a channel to transport chloride ions and water across cell membranes. The consequences are deleterious, system-wide, and [...] Read more.
In cystic fibrosis (CF), mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene disrupt the capacity of the encoded protein to function as a channel to transport chloride ions and water across cell membranes. The consequences are deleterious, system-wide, and immensely variable, even among patients with the same CFTR genotype. This underscores the need to characterize the mechanisms contributing to CF pathophysiology. Gene replacement and gene editing therapies have been pursued intensively and are expected to provide a one-time treatment for CF. However, gene replacement therapy is limited by the lack of efficient vectors to deliver functional copies of CFTR to cells without immunological complications, while gene editing technologies such as CRISPR/Cas9 are still in their infancy, mainly useful in somatic cells and limited by off-target insertions. Small molecule treatments targeted at potentiating or correcting CFTR have shown clinical benefits, but they are limited to a few CFTR mutations and insufficient to overcome challenges related to clinical heterogeneity. Transcriptome profiling approaches have emerged as robust tools capable of characterizing phenotypic variability and revealing novel molecular targets with therapeutic potential for CF. We summarize current insights gained through transcriptome profiling approaches in CF studies and recent advances in molecular therapeutics. Full article
(This article belongs to the Special Issue Cystic Fibrosis: Therapy and Genetics)
Show Figures

Figure 1

23 pages, 2421 KiB  
Review
Cystic Fibrosis Gene Therapy: Looking Back, Looking Forward
by Ashley L. Cooney, Paul B. McCray, Jr. and Patrick L. Sinn
Genes 2018, 9(11), 538; https://0-doi-org.brum.beds.ac.uk/10.3390/genes9110538 - 07 Nov 2018
Cited by 81 | Viewed by 24320
Abstract
Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that encodes a cAMP-regulated anion channel. Although CF is a multi-organ system disease, most people with CF die of progressive lung [...] Read more.
Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that encodes a cAMP-regulated anion channel. Although CF is a multi-organ system disease, most people with CF die of progressive lung disease that begins early in childhood and is characterized by chronic bacterial infection and inflammation. Nearly 90% of people with CF have at least one copy of the ΔF508 mutation, but there are hundreds of CFTR mutations that result in a range of disease severities. A CFTR gene replacement approach would be efficacious regardless of the disease-causing mutation. After the discovery of the CFTR gene in 1989, the in vitro proof-of-concept for gene therapy for CF was quickly established in 1990. In 1993, the first of many gene therapy clinical trials attempted to rescue the CF defect in airway epithelia. Despite the initial enthusiasm, there is still no FDA-approved gene therapy for CF. Here we discuss the history of CF gene therapy, from the discovery of the CFTR gene to current state-of-the-art gene delivery vector designs. While implementation of CF gene therapy has proven more challenging than initially envisioned; thanks to continued innovation, it may yet become a reality. Full article
(This article belongs to the Special Issue Cystic Fibrosis: Therapy and Genetics)
Show Figures

Figure 1

Back to TopTop