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Therapeutic Approaches for Cystic Fibrosis
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Therapeutic Approaches for Cystic Fibrosis

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: closed (31 March 2020) | Viewed by 109487

Special Issue Editors

Dr. Nicoletta Pedemonte

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Guest Editor
U.O.C. Genetica Medica, IRCCS Istituto Giannina Gaslini, Via Gerolamo Gaslini 5, 16147 Genova, Italy
Special Issues, Collections and Topics in MDPI journals
Dr. Darren Hutt

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Guest Editor
Department of Molecular Medicine, Scripps Research, NorthTorrey Pines Rd, La Jolla, CA 92037, USA

Special Issue Information

Dear Colleagues,

Cystic fibrosis (CF)-causing mutations have complex effects on the CF transmembrane conductance regulator (CFTR) protein, including disrupting its processing to and stability at the plasma membrane, as well as its chloride channel activity. Because of this complex disease etiology, a combination of CFTR modulators is required to rescue the trafficking and functional defects of disease-associated CFTR variants. Despite the success of these combinatorial therapeutics, some CF-causing mutations appear less responsive. For these CF variants, mutation-agnostic therapies have to be developed, such as ENAC inhibitors, activators of alternative chloride channels, and artificial anion transporters (anionophores), as well as cell-based and gene therapies.

This Special Issue on "Cystic Fibrosis" will gather reviews and original articles focused on novel therapeutic approaches to this disease at basic, translational, and clinical levels to provide expert insights and perspectives on advances in the field.

Dr. Nicoletta Pedemonte
Dr. Darren Hutt
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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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 channel
  • CFTR modulators
  • trafficking
  • proteostasis
  • function
  • siRNA screening
  • alternative chloride channel
  • airway epithelium
  • gene editing
  • cell-based approach

Published Papers (20 papers)

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Editorial

Jump to: Research, Review

8 pages, 209 KiB  
Editorial
Editorial: Special Issue on “Therapeutic Approaches for Cystic Fibrosis”
by Nicoletta Pedemonte
Int. J. Mol. Sci. 2020, 21(18), 6657; https://doi.org/10.3390/ijms21186657 - 11 Sep 2020
Cited by 1 | Viewed by 1905
Abstract
Cystic fibrosis (CF) is the most common lethal genetic disease in Caucasian populations, occurring in approximately 1 in 3000 newborns worldwide [...] Full article
(This article belongs to the Special Issue Therapeutic Approaches for Cystic Fibrosis)

Research

Jump to: Editorial, Review

18 pages, 2802 KiB  
Article
Phosphorylation of the Chaperone-Like HspB5 Rescues Trafficking and Function of F508del-CFTR
by Fanny Degrugillier, Abdel Aissat, Virginie Prulière-Escabasse, Lucie Bizard, Benjamin Simonneau, Xavier Decrouy, Chong Jiang, Daniela Rotin, Pascale Fanen and Stéphanie Simon
Int. J. Mol. Sci. 2020, 21(14), 4844; https://doi.org/10.3390/ijms21144844 - 8 Jul 2020
Cited by 5 | Viewed by 2663
Abstract
Cystic Fibrosis is a lethal monogenic autosomal recessive disease linked to mutations in Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein. The most frequent mutation is the deletion of phenylalanine at position 508 of the protein. This F508del-CFTR mutation leads to misfolded protein that [...] Read more.
Cystic Fibrosis is a lethal monogenic autosomal recessive disease linked to mutations in Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein. The most frequent mutation is the deletion of phenylalanine at position 508 of the protein. This F508del-CFTR mutation leads to misfolded protein that is detected by the quality control machinery within the endoplasmic reticulum and targeted for destruction by the proteasome. Modulating quality control proteins as molecular chaperones is a promising strategy for attenuating the degradation and stabilizing the mutant CFTR at the plasma membrane. Among the molecular chaperones, the small heat shock protein HspB1 and HspB4 were shown to promote degradation of F508del-CFTR. Here, we investigated the impact of HspB5 expression and phosphorylation on transport to the plasma membrane, function and stability of F508del-CFTR. We show that a phosphomimetic form of HspB5 increases the transport to the plasma membrane, function and stability of F508del-CFTR. These activities are further enhanced in presence of therapeutic drugs currently used for the treatment of cystic fibrosis (VX-770/Ivacaftor, VX-770+VX-809/Orkambi). Overall, this study highlights the beneficial effects of a phosphorylated form of HspB5 on F508del-CFTR rescue and its therapeutic potential in cystic fibrosis. Full article
(This article belongs to the Special Issue Therapeutic Approaches for Cystic Fibrosis)
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19 pages, 3604 KiB  
Article
GM1 as Adjuvant of Innovative Therapies for Cystic Fibrosis Disease
by Giulia Mancini, Nicoletta Loberto, Debora Olioso, Maria Cristina Dechecchi, Giulio Cabrini, Laura Mauri, Rosaria Bassi, Domitilla Schiumarini, Elena Chiricozzi, Giuseppe Lippi, Emanuela Pesce, Sandro Sonnino, Nicoletta Pedemonte, Anna Tamanini and Massimo Aureli
Int. J. Mol. Sci. 2020, 21(12), 4486; https://doi.org/10.3390/ijms21124486 - 24 Jun 2020
Cited by 10 | Viewed by 2815
Abstract
Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein is expressed at the apical plasma membrane (PM) of different epithelial cells. The most common mutation responsible for the onset of cystic fibrosis (CF), F508del, inhibits the biosynthesis and transport of the protein at PM, and [...] Read more.
Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein is expressed at the apical plasma membrane (PM) of different epithelial cells. The most common mutation responsible for the onset of cystic fibrosis (CF), F508del, inhibits the biosynthesis and transport of the protein at PM, and also presents gating and stability defects of the membrane anion channel upon its rescue by the use of correctors and potentiators. This prompted a multiple drug strategy for F508delCFTR aimed simultaneously at its rescue, functional potentiation and PM stabilization. Since ganglioside GM1 is involved in the functional stabilization of transmembrane proteins, we investigated its role as an adjuvant to increase the effectiveness of CFTR modulators. According to our results, we found that GM1 resides in the same PM microenvironment as CFTR. In CF cells, the expression of the mutated channel is accompanied by a decrease in the PM GM1 content. Interestingly, by the exogenous administration of GM1, it becomes a component of the PM, reducing the destabilizing effect of the potentiator VX-770 on rescued CFTR protein expression/function and improving its stabilization. This evidence could represent a starting point for developing innovative therapeutic strategies based on the co-administration of GM1, correctors and potentiators, with the aim of improving F508del CFTR function. Full article
(This article belongs to the Special Issue Therapeutic Approaches for Cystic Fibrosis)
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23 pages, 7863 KiB  
Article
The Effect of Sodium Bicarbonate, a Beneficial Adjuvant Molecule in Cystic Fibrosis, on Bronchial Epithelial Cells Expressing a Wild-Type or Mutant CFTR Channel
by Ilona Gróf, Alexandra Bocsik, András Harazin, Ana Raquel Santa-Maria, Gaszton Vizsnyiczai, Lilla Barna, Lóránd Kiss, Gabriella Fűr, Zoltán Rakonczay, Jr., Rita Ambrus, Piroska Szabó-Révész, Fabien Gosselet, Pongsiri Jaikumpun, Hajnalka Szabó, Ákos Zsembery and Mária A. Deli
Int. J. Mol. Sci. 2020, 21(11), 4024; https://doi.org/10.3390/ijms21114024 - 4 Jun 2020
Cited by 17 | Viewed by 4143
Abstract
Clinical and experimental results with inhaled sodium bicarbonate as an adjuvant therapy in cystic fibrosis (CF) are promising due to its mucolytic and bacteriostatic properties, but its direct effect has not been studied on respiratory epithelial cells. Our aim was to establish and [...] Read more.
Clinical and experimental results with inhaled sodium bicarbonate as an adjuvant therapy in cystic fibrosis (CF) are promising due to its mucolytic and bacteriostatic properties, but its direct effect has not been studied on respiratory epithelial cells. Our aim was to establish and characterize co-culture models of human CF bronchial epithelial (CFBE) cell lines expressing a wild-type (WT) or mutant (deltaF508) CF transmembrane conductance regulator (CFTR) channel with human vascular endothelial cells and investigate the effects of bicarbonate. Vascular endothelial cells induced better barrier properties in CFBE cells as reflected by the higher resistance and lower permeability values. Activation of CFTR by cAMP decreased the electrical resistance in WT but not in mutant CFBE cell layers confirming the presence and absence of functional channels, respectively. Sodium bicarbonate (100 mM) was well-tolerated by CFBE cells: it slightly reduced the impedance of WT but not that of the mutant CFBE cells. Sodium bicarbonate significantly decreased the more-alkaline intracellular pH of the mutant CFBE cells, while the barrier properties of the models were only minimally changed. These observations indicate that sodium bicarbonate is beneficial to deltaF508-CFTR expressing CFBE cells. Thus, sodium bicarbonate may have a direct therapeutic effect on the bronchial epithelium. Full article
(This article belongs to the Special Issue Therapeutic Approaches for Cystic Fibrosis)
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8 pages, 1437 KiB  
Communication
Mechanical Properties of Human Bronchial Epithelial Cells Expressing Wt- and Mutant CFTR
by Ana P. Carapeto, Miguel V. Vitorino, João D. Santos, Sofia S. Ramalho, Tiago Robalo, Mário S. Rodrigues and Carlos M. Farinha
Int. J. Mol. Sci. 2020, 21(8), 2916; https://doi.org/10.3390/ijms21082916 - 21 Apr 2020
Cited by 8 | Viewed by 2919
Abstract
Cystic fibrosis (CF) is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). A single recessive mutation, the deletion of phenylalanine 508 (F508del), causes severe CF and resides on 70% of mutant chromosomes. Disorganization of the actin cytoskeleton [...] Read more.
Cystic fibrosis (CF) is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). A single recessive mutation, the deletion of phenylalanine 508 (F508del), causes severe CF and resides on 70% of mutant chromosomes. Disorganization of the actin cytoskeleton has been previously reported in relation to the CF phenotype. In this work, we aimed to understand this alteration by means of Atomic Force Microscopy and Force Feedback Microscopy investigation of mechanical properties of cystic fibrosis bronchial epithelial (CFBE) cells stably transduced with either wild type (wt-) or F508del-CFTR. We show here that the expression of mutant CFTR causes a decrease in the cell’s apparent Young modulus as compared to the expression of the wt protein. Full article
(This article belongs to the Special Issue Therapeutic Approaches for Cystic Fibrosis)
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17 pages, 7602 KiB  
Article
Pharmacological Inhibition and Activation of the Ca2+ Activated Cl− Channel TMEM16A
by Raquel Centeio, Inês Cabrita, Roberta Benedetto, Khaoula Talbi, Jiraporn Ousingsawat, Rainer Schreiber, John K. Sullivan and Karl Kunzelmann
Int. J. Mol. Sci. 2020, 21(7), 2557; https://doi.org/10.3390/ijms21072557 - 7 Apr 2020
Cited by 38 | Viewed by 4187
Abstract
TMEM16A is a Ca2+ activated Cl− channel with important functions in airways, intestine, and other epithelial organs. Activation of TMEM16A is proposed as a therapy in cystic fibrosis (CF) to reinstall airway Cl− secretion and to enhance airway surface liquid [...] Read more.
TMEM16A is a Ca2+ activated Cl− channel with important functions in airways, intestine, and other epithelial organs. Activation of TMEM16A is proposed as a therapy in cystic fibrosis (CF) to reinstall airway Cl− secretion and to enhance airway surface liquid (ASL). This CFTR-agnostic approach is thought to improve mucociliary clearance and lung function in CF. This could indeed improve ASL, however, mucus release and airway contraction may also be induced by activators of TMEM16A, particularly in inflamed airways of patients with asthma, COPD, or CF. Currently, both activators and inhibitors of TMEM16A are developed and examined in different types of tissues. Here we compare activation and inhibition of endogenous and overexpressed TMEM16A and analyze potential off-target effects. The three well-known blockers benzbromarone, niclosamide, and Ani9 inhibited both TMEM16A and ATP-induced Ca2+ increase by variable degrees, depending on the cell type. Niclosamide, while blocking Ca2+ activated TMEM16A, also induced a subtle but significant Ca2+ store release and inhibited store-operated Ca2+ influx. Niclosamide, benzbromarone and Ani9 also affected TMEM16F whole cell currents, indicating limited specificity for these inhibitors. The compounds Eact, cinnamaldehyde, and melittin, as well as the phosphatidylinositol diC8-PIP2 are the reported activators of TMEM16A. However, the compounds were unable to activate endogenous TMEM16A in HT29 colonic epithelial cells. In contrast, TMEM16A overexpressed in HEK293 cells was potently stimulated by these activators. We speculate that overexpressed TMEM16A might have a better accessibility to intracellular Ca2+, which causes spontaneous activity even at basal intracellular Ca2+ concentrations. Small molecules may therefore potentiate pre-stimulated TMEM16A currents, but may otherwise fail to activate silent endogenous TMEM16A. Full article
(This article belongs to the Special Issue Therapeutic Approaches for Cystic Fibrosis)
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12 pages, 1074 KiB  
Article
Treatment of Cystic Fibrosis Patients Homozygous for F508del with Lumacaftor-Ivacaftor (Orkambi®) Restores Defective CFTR Channel Function in Circulating Mononuclear Cells
by Maria Favia, Crescenzio Gallo, Lorenzo Guerra, Domenica De Venuto, Anna Diana, Angela Maria Polizzi, Pasqualina Montemurro, Maria Addolorata Mariggiò, Giuseppina Leonetti, Antonio Manca, Valeria Casavola and Massimo Conese
Int. J. Mol. Sci. 2020, 21(7), 2398; https://doi.org/10.3390/ijms21072398 - 31 Mar 2020
Cited by 15 | Viewed by 3898
Abstract
The treatment of cystic fibrosis (CF) patients homozygous for the F508del mutation with Orkambi®, a combination of a corrector (lumacaftor) and a potentiator (ivacaftor) of the mutated CFTR protein, resulted in some amelioration of the respiratory function. However, a great variability [...] Read more.
The treatment of cystic fibrosis (CF) patients homozygous for the F508del mutation with Orkambi®, a combination of a corrector (lumacaftor) and a potentiator (ivacaftor) of the mutated CFTR protein, resulted in some amelioration of the respiratory function. However, a great variability in the clinical response was also observed. The aim of this study was to evaluate the response to Orkambi® in a small cohort of F508del/F508del patients (n = 14) in terms of clinical and laboratory parameters, including ex vivo CFTR activity in mononuclear cells (MNCs), during a 12-month treatment. Patients responded with an increase in percent predicted forced expiratory volume in 1 s (FEV1%) and body mass index (BMI) as well as with a decrease in white blood cell (WBC) total counts and serum C-reactive protein (CRP) levels, although not significantly. Sweat chloride and CFTR-dependent chloride efflux were found to decrease and increase, respectively, as compared with pre-therapy values. CFTR and BMI showed a statistically significant correlation during Orkambi® treatment. Clustering analysis showed that CFTR, BMI, sweat chloride, FEV1%, and WBC were strongly associated. These data support the notion that CFTR-dependent chloride efflux in MNCs should be investigated as a sensitive outcome measure of Orkambi® treatment in CF patients. Full article
(This article belongs to the Special Issue Therapeutic Approaches for Cystic Fibrosis)
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14 pages, 2173 KiB  
Article
Small Molecule Anion Carriers Correct Abnormal Airway Surface Liquid Properties in Cystic Fibrosis Airway Epithelia
by Ambra Gianotti, Valeria Capurro, Livia Delpiano, Marcin Mielczarek, María García-Valverde, Israel Carreira-Barral, Alessandra Ludovico, Michele Fiore, Debora Baroni, Oscar Moran, Roberto Quesada and Emanuela Caci
Int. J. Mol. Sci. 2020, 21(4), 1488; https://doi.org/10.3390/ijms21041488 - 21 Feb 2020
Cited by 22 | Viewed by 3560
Abstract
Cystic fibrosis (CF) is a genetic disease characterized by the lack of cystic fibrosis transmembrane conductance regulator (CFTR) protein expressed in epithelial cells. The resulting defective chloride and bicarbonate secretion and imbalance of the transepithelial homeostasis lead to abnormal airway surface liquid (ASL) [...] Read more.
Cystic fibrosis (CF) is a genetic disease characterized by the lack of cystic fibrosis transmembrane conductance regulator (CFTR) protein expressed in epithelial cells. The resulting defective chloride and bicarbonate secretion and imbalance of the transepithelial homeostasis lead to abnormal airway surface liquid (ASL) composition and properties. The reduced ASL volume impairs ciliary beating with the consequent accumulation of sticky mucus. This situation prevents the normal mucociliary clearance, favouring the survival and proliferation of bacteria and contributing to the genesis of CF lung disease. Here, we have explored the potential of small molecules capable of facilitating the transmembrane transport of chloride and bicarbonate in order to replace the defective transport activity elicited by CFTR in CF airway epithelia. Primary human bronchial epithelial cells obtained from CF and non-CF patients were differentiated into a mucociliated epithelia in order to assess the effects of our compounds on some key properties of ASL. The treatment of these functional models with non-toxic doses of the synthetic anionophores improved the periciliary fluid composition, reducing the fluid re-absorption, correcting the ASL pH and reducing the viscosity of the mucus, thus representing promising drug candidates for CF therapy. Full article
(This article belongs to the Special Issue Therapeutic Approaches for Cystic Fibrosis)
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20 pages, 2819 KiB  
Article
Unravelling the Regions of Mutant F508del-CFTR More Susceptible to the Action of Four Cystic Fibrosis Correctors
by Giulia Amico, Chiara Brandas, Oscar Moran and Debora Baroni
Int. J. Mol. Sci. 2019, 20(21), 5463; https://doi.org/10.3390/ijms20215463 - 1 Nov 2019
Cited by 15 | Viewed by 6332
Abstract
Cystic fibrosis (CF) is a genetic disease associated with the defective function of the cystic fibrosis transmembrane conductance regulator (CFTR) protein that causes obstructive disease and chronic bacterial infections in airway epithelia. The most prevalent CF-causing mutation, the deletion of phenylalanine at position [...] Read more.
Cystic fibrosis (CF) is a genetic disease associated with the defective function of the cystic fibrosis transmembrane conductance regulator (CFTR) protein that causes obstructive disease and chronic bacterial infections in airway epithelia. The most prevalent CF-causing mutation, the deletion of phenylalanine at position 508 (F508del), leads to CFTR misfolding, trafficking defects and premature degradation. A number of correctors that are able to partially rescue F508del-CFTR processing defects have been identified. Clinical trials have demonstrated that, unfortunately, mono-therapy with the best correctors identified to date does not ameliorate lung function or sweat chloride concentration in homozygous F508del patients. Understanding the mechanisms exerted by currently available correctors to increase mutant F508del-CFTR expression is essential for the development of new CF-therapeutics. We investigated the activity of correctors on the mutant F508del and wild type (WT) CFTR to identify the protein domains whose expression is mostly affected by the action of correctors, and we investigated their mechanisms of action. We found that the four correctors under study, lumacaftor (VX809), the quinazoline derivative VX325, the bithiazole compound corr4a, and the new molecule tezacaftor (VX661), do not influence either the total expression or the maturation of the WT-CFTR transiently expressed in human embryonic kidney 293 (HEK293) cells. Contrarily, they significantly enhance the expression and the maturation of the full length F508del molecule. Three out of four correctors, VX809, VX661 and VX325, seem to specifically improve the expression and the maturation of the mutant CFTR N-half (M1N1, residues 1–633). By contrast, the CFTR C-half (M2N2, residues 837–1480) appears to be the region mainly affected by corr4a. VX809 was shown to stabilize both the WT- and F508del-CFTR N-half isoforms, while VX661 and VX325 demonstrated the ability to enhance the stability only of the mutant F508del polypeptide. Full article
(This article belongs to the Special Issue Therapeutic Approaches for Cystic Fibrosis)
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Review

Jump to: Editorial, Research

13 pages, 907 KiB  
Review
Gene Therapy for Cystic Fibrosis: Progress and Challenges of Genome Editing
by Giulia Maule, Daniele Arosio and Anna Cereseto
Int. J. Mol. Sci. 2020, 21(11), 3903; https://doi.org/10.3390/ijms21113903 - 30 May 2020
Cited by 38 | Viewed by 14748
Abstract
Since the early days of its conceptualization and application, human gene transfer held the promise of a permanent solution to genetic diseases including cystic fibrosis (CF). This field went through alternated periods of enthusiasm and distrust. The development of refined technologies allowing site [...] Read more.
Since the early days of its conceptualization and application, human gene transfer held the promise of a permanent solution to genetic diseases including cystic fibrosis (CF). This field went through alternated periods of enthusiasm and distrust. The development of refined technologies allowing site specific modification with programmable nucleases highly revived the gene therapy field. CRISPR nucleases and derived technologies tremendously facilitate genome manipulation offering diversified strategies to reverse mutations. Here we discuss the advancement of gene therapy, from therapeutic nucleic acids to genome editing techniques, designed to reverse genetic defects in CF. We provide a roadmap through technologies and strategies tailored to correct different types of mutations in the cystic fibrosis transmembrane regulator (CFTR) gene, and their applications for the development of experimental models valuable for the advancement of CF therapies. Full article
(This article belongs to the Special Issue Therapeutic Approaches for Cystic Fibrosis)
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21 pages, 2995 KiB  
Review
The Role of MicroRNA in the Airway Surface Liquid Homeostasis
by Nilay Mitash, Joshua E. Donovan and Agnieszka Swiatecka-Urban
Int. J. Mol. Sci. 2020, 21(11), 3848; https://doi.org/10.3390/ijms21113848 - 28 May 2020
Cited by 19 | Viewed by 4140
Abstract
Mucociliary clearance, mediated by a coordinated function of cilia bathing in the airway surface liquid (ASL) on the surface of airway epithelium, protects the host from inhaled pathogens and is an essential component of the innate immunity. ASL is composed of the superficial [...] Read more.
Mucociliary clearance, mediated by a coordinated function of cilia bathing in the airway surface liquid (ASL) on the surface of airway epithelium, protects the host from inhaled pathogens and is an essential component of the innate immunity. ASL is composed of the superficial mucus layer and the deeper periciliary liquid. Ion channels, transporters, and pumps coordinate the transcellular and paracellular movement of ions and water to maintain the ASL volume and mucus hydration. microRNA (miRNA) is a class of non-coding, short single-stranded RNA regulating gene expression by post-transcriptional mechanisms. miRNAs have been increasingly recognized as essential regulators of ion channels and transporters responsible for ASL homeostasis. miRNAs also influence the airway host defense. We summarize the most up-to-date information on the role of miRNAs in ASL homeostasis and host–pathogen interactions in the airway and discuss concepts for miRNA-directed therapy. Full article
(This article belongs to the Special Issue Therapeutic Approaches for Cystic Fibrosis)
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34 pages, 14946 KiB  
Review
Synthesis and Therapeutic Applications of Iminosugars in Cystic Fibrosis
by Anna Esposito, Daniele D’Alonzo, Maria De Fenza, Eliana De Gregorio, Anna Tamanini, Giuseppe Lippi, Maria Cristina Dechecchi and Annalisa Guaragna
Int. J. Mol. Sci. 2020, 21(9), 3353; https://doi.org/10.3390/ijms21093353 - 9 May 2020
Cited by 24 | Viewed by 4433
Abstract
Iminosugars are sugar analogues endowed with a high pharmacological potential. The wide range of biological activities exhibited by these glycomimetics associated with their excellent drug profile make them attractive therapeutic candidates for several medical interventions. The ability of iminosugars to act as inhibitors [...] Read more.
Iminosugars are sugar analogues endowed with a high pharmacological potential. The wide range of biological activities exhibited by these glycomimetics associated with their excellent drug profile make them attractive therapeutic candidates for several medical interventions. The ability of iminosugars to act as inhibitors or enhancers of carbohydrate-processing enzymes suggests their potential use as therapeutics for the treatment of cystic fibrosis (CF). Herein we review the most relevant advances in the field, paying attention to both the chemical synthesis of the iminosugars and their biological evaluations, resulting from in vitro and in vivo assays. Starting from the example of the marketed drug NBDNJ (N-butyl deoxynojirimycin), a variety of iminosugars have exhibited the capacity to rescue the trafficking of F508del-CFTR (deletion of F508 residue in the CF transmembrane conductance regulator), either alone or in combination with other correctors. Interesting results have also been obtained when iminosugars were considered as anti-inflammatory agents in CF lung disease. The data herein reported demonstrate that iminosugars hold considerable potential to be applied for both therapeutic purposes. Full article
(This article belongs to the Special Issue Therapeutic Approaches for Cystic Fibrosis)
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23 pages, 1288 KiB  
Review
Immunomodulation in Cystic Fibrosis: Why and How?
by Vincent D. Giacalone, Brian S. Dobosh, Amit Gaggar, Rabindra Tirouvanziam and Camilla Margaroli
Int. J. Mol. Sci. 2020, 21(9), 3331; https://doi.org/10.3390/ijms21093331 - 8 May 2020
Cited by 13 | Viewed by 8051
Abstract
Cystic fibrosis (CF) lung disease is characterized by unconventional mechanisms of inflammation, implicating a chronic immune response dominated by innate immune cells. Historically, therapeutic development has focused on the mutated cystic fibrosis transmembrane conductance regulator (CFTR), leading to the discovery of small molecules [...] Read more.
Cystic fibrosis (CF) lung disease is characterized by unconventional mechanisms of inflammation, implicating a chronic immune response dominated by innate immune cells. Historically, therapeutic development has focused on the mutated cystic fibrosis transmembrane conductance regulator (CFTR), leading to the discovery of small molecules aiming at modulating and potentiating the presence and activity of CFTR at the plasma membrane. However, treatment burden sustained by CF patients, side effects of current medications, and recent advances in other therapeutic areas have highlighted the need to develop novel disease targeting of the inflammatory component driving CF lung damage. Furthermore, current issues with standard treatment emphasize the need for directed lung therapies that could minimize systemic side effects. Here, we summarize current treatment used to target immune cells in the lungs, and highlight potential benefits and caveats of novel therapeutic strategies. Full article
(This article belongs to the Special Issue Therapeutic Approaches for Cystic Fibrosis)
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Graphical abstract

28 pages, 3937 KiB  
Review
What Role Does CFTR Play in Development, Differentiation, Regeneration and Cancer?
by Margarida D. Amaral, Margarida C. Quaresma and Ines Pankonien
Int. J. Mol. Sci. 2020, 21(9), 3133; https://doi.org/10.3390/ijms21093133 - 29 Apr 2020
Cited by 41 | Viewed by 8942
Abstract
One of the key features associated with the substantial increase in life expectancy for individuals with CF is an elevated predisposition to cancer, firmly established by recent studies involving large cohorts. With the recent advances in cystic fibrosis transmembrane conductance regulator (CFTR) modulator [...] Read more.
One of the key features associated with the substantial increase in life expectancy for individuals with CF is an elevated predisposition to cancer, firmly established by recent studies involving large cohorts. With the recent advances in cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies and the increased long-term survival rate of individuals with cystic fibrosis (CF), this is a novel challenge emerging at the forefront of this disease. However, the mechanisms linking dysfunctional CFTR to carcinogenesis have yet to be unravelled. Clues to this challenging open question emerge from key findings in an increasing number of studies showing that CFTR plays a role in fundamental cellular processes such as foetal development, epithelial differentiation/polarization, and regeneration, as well as in epithelial–mesenchymal transition (EMT). Here, we provide state-of-the-art descriptions on the moonlight roles of CFTR in these processes, highlighting how they can contribute to novel therapeutic strategies. However, such roles are still largely unknown, so we need rapid progress in the elucidation of the underlying mechanisms to find the answers and thus tailor the most appropriate therapeutic approaches. Full article
(This article belongs to the Special Issue Therapeutic Approaches for Cystic Fibrosis)
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21 pages, 1011 KiB  
Review
Cystic Fibrosis, CFTR, and Colorectal Cancer
by Patricia Scott, Kyle Anderson, Mekhla Singhania and Robert Cormier
Int. J. Mol. Sci. 2020, 21(8), 2891; https://doi.org/10.3390/ijms21082891 - 21 Apr 2020
Cited by 62 | Viewed by 9639
Abstract
Cystic fibrosis (CF), caused by biallelic inactivating mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, has recently been categorized as a familial colorectal cancer (CRC) syndrome. CF patients are highly susceptible to early, aggressive colorectal tumor development. Endoscopic screening [...] Read more.
Cystic fibrosis (CF), caused by biallelic inactivating mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, has recently been categorized as a familial colorectal cancer (CRC) syndrome. CF patients are highly susceptible to early, aggressive colorectal tumor development. Endoscopic screening studies have revealed that by the age of forty 50% of CF patients will develop adenomas, with 25% developing aggressive advanced adenomas, some of which will have already advanced to adenocarcinomas. This enhanced risk has led to new CF colorectal cancer screening recommendations, lowering the initiation of endoscopic screening to age forty in CF patients, and to age thirty in organ transplant recipients. The enhanced risk for CRC also extends to the millions of people (more than 10 million in the US) who are heterozygous carriers of CFTR gene mutations. Further, lowered expression of CFTR is reported in sporadic CRC, where downregulation of CFTR is associated with poor survival. Mechanisms underlying the actions of CFTR as a tumor suppressor are not clearly understood. Dysregulation of Wnt/β-catenin signaling and disruption of intestinal stem cell homeostasis and intestinal barrier integrity, as well as intestinal dysbiosis, immune cell infiltration, stress responses, and intestinal inflammation have all been reported in human CF patients and in animal models. Notably, the development of new drug modalities to treat non-gastrointestinal pathologies in CF patients, especially pulmonary disease, offers hope that these drugs could be repurposed for gastrointestinal cancers. Full article
(This article belongs to the Special Issue Therapeutic Approaches for Cystic Fibrosis)
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21 pages, 3103 KiB  
Review
Recent Strategic Advances in CFTR Drug Discovery: An Overview
by Marco Rusnati, Pasqualina D’Ursi, Nicoletta Pedemonte, Chiara Urbinati, Robert C. Ford, Elena Cichero, Matteo Uggeri, Alessandro Orro and Paola Fossa
Int. J. Mol. Sci. 2020, 21(7), 2407; https://doi.org/10.3390/ijms21072407 - 31 Mar 2020
Cited by 7 | Viewed by 4488
Abstract
Cystic fibrosis transmembrane conductance regulator (CFTR)-rescuing drugs have already transformed cystic fibrosis (CF) from a fatal disease to a treatable chronic condition. However, new-generation drugs able to bind CFTR with higher specificity/affinity and to exert stronger therapeutic benefits and fewer side effects are [...] Read more.
Cystic fibrosis transmembrane conductance regulator (CFTR)-rescuing drugs have already transformed cystic fibrosis (CF) from a fatal disease to a treatable chronic condition. However, new-generation drugs able to bind CFTR with higher specificity/affinity and to exert stronger therapeutic benefits and fewer side effects are still awaited. Computational methods and biosensors have become indispensable tools in the process of drug discovery for many important human pathologies. Instead, they have been used only piecemeal in CF so far, calling for their appropriate integration with well-tried CF biochemical and cell-based models to speed up the discovery of new CFTR-rescuing drugs. This review will give an overview of the available structures and computational models of CFTR and of the biosensors, biochemical and cell-based assays already used in CF-oriented studies. It will also give the reader some insights about how to integrate these tools as to improve the efficiency of the drug discovery process targeted to CFTR. Full article
(This article belongs to the Special Issue Therapeutic Approaches for Cystic Fibrosis)
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16 pages, 1387 KiB  
Review
TMEM16A: An Alternative Approach to Restoring Airway Anion Secretion in Cystic Fibrosis?
by Henry Danahay and Martin Gosling
Int. J. Mol. Sci. 2020, 21(7), 2386; https://doi.org/10.3390/ijms21072386 - 30 Mar 2020
Cited by 24 | Viewed by 4515
Abstract
The concept that increasing airway hydration leads to improvements in mucus clearance and lung function in cystic fibrosis has been clinically validated with osmotic agents such as hypertonic saline and more convincingly with cystic fibrosis transmembrane conductance regulator (CFTR) repair therapies. Although rapidly [...] Read more.
The concept that increasing airway hydration leads to improvements in mucus clearance and lung function in cystic fibrosis has been clinically validated with osmotic agents such as hypertonic saline and more convincingly with cystic fibrosis transmembrane conductance regulator (CFTR) repair therapies. Although rapidly becoming the standard of care in cystic fibrosis (CF), current CFTR modulators do not treat all patients nor do they restore the rate of decline in lung function to normal levels. As such, novel approaches are still required to ensure all with CF have effective therapies. Although CFTR plays a fundamental role in the regulation of fluid secretion across the airway mucosa, there are other ion channels and transporters that represent viable targets for future therapeutics. In this review article we will summarise the current progress with CFTR-independent approaches to restoring mucosal hydration, including epithelial sodium channel (ENaC) blockade and modulators of SLC26A9. A particular emphasis is given to modulation of the airway epithelial calcium-activated chloride channel (CaCC), TMEM16A, as there is controversy regarding whether it should be positively or negatively modulated. This is discussed in light of a recent report describing for the first time bona fide TMEM16A potentiators and their positive effects upon epithelial fluid secretion and mucus clearance. Full article
(This article belongs to the Special Issue Therapeutic Approaches for Cystic Fibrosis)
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19 pages, 891 KiB  
Review
Alpha-1 Antitrypsin—A Target for MicroRNA-Based Therapeutic Development for Cystic Fibrosis
by Alison M.D. Hunt, Arlene M.A. Glasgow, Hilary Humphreys and Catherine M. Greene
Int. J. Mol. Sci. 2020, 21(3), 836; https://doi.org/10.3390/ijms21030836 - 28 Jan 2020
Cited by 11 | Viewed by 3555
Abstract
Cystic fibrosis (CF) is an autosomal recessive genetic disorder arising from mutations to the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Disruption to normal ion homeostasis in the airway results in impaired mucociliary clearance, leaving the lung more vulnerable to recurrent [...] Read more.
Cystic fibrosis (CF) is an autosomal recessive genetic disorder arising from mutations to the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Disruption to normal ion homeostasis in the airway results in impaired mucociliary clearance, leaving the lung more vulnerable to recurrent and chronic bacterial infections. The CF lung endures an excess of neutrophilic inflammation, and whilst neutrophil serine proteases are a crucial part of the innate host defence to infection, a surplus of neutrophil elastase (NE) is understood to create a net destructive effect. Alpha-1 antitrypsin (A1AT) is a key antiprotease in the control of NE protease activity but is ineffective in the CF lung due to the huge imbalance of NE levels. Therapeutic strategies to boost levels of protective antiproteases such as A1AT in the lung remain an attractive research strategy to limit the damage from excess protease activity. microRNAs are small non-coding RNA molecules that bind specific cognate sequences to inhibit expression of target mRNAs. The inhibition of miRNAs which target the SERPINA1 (A1AT-encoding gene) mRNA represents a novel therapeutic approach for CF inflammation. This could involve the delivery of antagomirs that bind and sequester the target miRNA, or target site blockers that bind miRNA recognition elements within the target mRNA to prevent miRNA interaction. Therefore, miRNA targeted therapies offer an alternative strategy to drive endogenous A1AT production and thus supplement the antiprotease shield of the CF lung. Full article
(This article belongs to the Special Issue Therapeutic Approaches for Cystic Fibrosis)
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25 pages, 1615 KiB  
Review
Regulation of CFTR Biogenesis by the Proteostatic Network and Pharmacological Modulators
by Samuel Estabrooks and Jeffrey L. Brodsky
Int. J. Mol. Sci. 2020, 21(2), 452; https://doi.org/10.3390/ijms21020452 - 10 Jan 2020
Cited by 27 | Viewed by 5487
Abstract
Cystic fibrosis (CF) is the most common lethal inherited disease among Caucasians in North America and a significant portion of Europe. The disease arises from one of many mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator, or CFTR. The most [...] Read more.
Cystic fibrosis (CF) is the most common lethal inherited disease among Caucasians in North America and a significant portion of Europe. The disease arises from one of many mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator, or CFTR. The most common disease-associated allele, F508del, along with several other mutations affect the folding, transport, and stability of CFTR as it transits from the endoplasmic reticulum (ER) to the plasma membrane, where it functions primarily as a chloride channel. Early data demonstrated that F508del CFTR is selected for ER associated degradation (ERAD), a pathway in which misfolded proteins are recognized by ER-associated molecular chaperones, ubiquitinated, and delivered to the proteasome for degradation. Later studies showed that F508del CFTR that is rescued from ERAD and folds can alternatively be selected for enhanced endocytosis and lysosomal degradation. A number of other disease-causing mutations in CFTR also undergo these events. Fortunately, pharmacological modulators of CFTR biogenesis can repair CFTR, permitting its folding, escape from ERAD, and function at the cell surface. In this article, we review the many cellular checkpoints that monitor CFTR biogenesis, discuss the emergence of effective treatments for CF, and highlight future areas of research on the proteostatic control of CFTR. Full article
(This article belongs to the Special Issue Therapeutic Approaches for Cystic Fibrosis)
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21 pages, 1752 KiB  
Review
Mycobacterium abscessus, an Emerging and Worrisome Pathogen among Cystic Fibrosis Patients
by Giulia Degiacomi, José Camilla Sammartino, Laurent Roberto Chiarelli, Olga Riabova, Vadim Makarov and Maria Rosalia Pasca
Int. J. Mol. Sci. 2019, 20(23), 5868; https://doi.org/10.3390/ijms20235868 - 22 Nov 2019
Cited by 89 | Viewed by 8265
Abstract
Nontuberculous mycobacteria (NTM) have recently emerged as important pathogens among cystic fibrosis (CF) patients worldwide. Mycobacterium abscessus is becoming the most worrisome NTM in this cohort of patients and recent findings clarified why this pathogen is so prone to this disease. M. abscessus [...] Read more.
Nontuberculous mycobacteria (NTM) have recently emerged as important pathogens among cystic fibrosis (CF) patients worldwide. Mycobacterium abscessus is becoming the most worrisome NTM in this cohort of patients and recent findings clarified why this pathogen is so prone to this disease. M. abscessus drug therapy takes up to 2 years and its failure causes an accelerated lung function decline. The M. abscessus colonization of lung alveoli begins with smooth strains producing glycopeptidolipids and biofilm, whilst in the invasive infection, “rough” mutants are responsible for the production of trehalose dimycolate, and consequently, cording formation. Human-to-human M. abscessus transmission was demonstrated among geographically separated CF patients by whole-genome sequencing of clinical isolates worldwide. Using a M. abscessus infected CF zebrafish model, it was demonstrated that CFTR (cystic fibrosis transmembrane conductance regulator) dysfunction seems to have a specific role in the immune control of M. abscessus infections only. This pathogen is also intrinsically resistant to many drugs, thanks to its physiology and to the acquisition of new mechanisms of drug resistance. Few new compounds or drug formulations active against M. abscessus are present in preclinical and clinical development, but recently alternative strategies have been investigated, such as phage therapy and the use of β-lactamase inhibitors. Full article
(This article belongs to the Special Issue Therapeutic Approaches for Cystic Fibrosis)
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