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Therapeutic Approaches for Cystic Fibrosis 2.0
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Therapeutic Approaches for Cystic Fibrosis 2.0

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 2021) | Viewed by 55936

Special Issue Editor

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

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
Guest Editor

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Keywords

  • CFTR channel
  • CFTR modulators
  • trafficking
  • proteostasis
  • function
  • siRNA screening
  • alternative chloride channel
  • airway epithelium
  • gene editing
  • cell-based approach

Published Papers (15 papers)

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Research

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16 pages, 14799 KiB  
Article
Synergy in Cystic Fibrosis Therapies: Targeting SLC26A9
by Madalena C. Pinto, Margarida C. Quaresma, Iris A. L. Silva, Violeta Railean, Sofia S. Ramalho and Margarida D. Amaral
Int. J. Mol. Sci. 2021, 22(23), 13064; https://doi.org/10.3390/ijms222313064 - 2 Dec 2021
Cited by 13 | Viewed by 2542
Abstract
SLC26A9, a constitutively active Cl− transporter, has gained interest over the past years as a relevant disease modifier in several respiratory disorders including Cystic Fibrosis (CF), asthma, and non-CF bronchiectasis. SLC26A9 contributes to epithelial Cl− secretion, thus preventing mucus obstruction under [...] Read more.
SLC26A9, a constitutively active Cl− transporter, has gained interest over the past years as a relevant disease modifier in several respiratory disorders including Cystic Fibrosis (CF), asthma, and non-CF bronchiectasis. SLC26A9 contributes to epithelial Cl− secretion, thus preventing mucus obstruction under inflammatory conditions. Additionally, SLC26A9 was identified as a CF gene modifier, and its polymorphisms were shown to correlate with the response to drugs modulating CFTR, the defective protein in CF. Here, we aimed to investigate the relationship between SLC26A9 and CFTR, and its role in CF pathogenesis. Our data show that SLC26A9 expression contributes to enhanced CFTR expression and function. While knocking-down SLC26A9 in human bronchial cells leads to lower wt- and F508del-CFTR expression, function, and response to CFTR correctors, the opposite occurs upon its overexpression, highlighting SLC26A9 relevance for CF. Accordingly, F508del-CFTR rescue by the most efficient correctors available is further enhanced by increasing SLC26A9 expression. Interestingly, SLC26A9 overexpression does not increase the PM expression of non-F508del CFTR traffic mutants, namely those unresponsive to corrector drugs. Altogether, our data indicate that SLC26A9 stabilizes CFTR at the ER level and that the efficacy of CFTR modulator drugs may be further enhanced by increasing its expression. Full article
(This article belongs to the Special Issue Therapeutic Approaches for Cystic Fibrosis 2.0)
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22 pages, 38169 KiB  
Article
Comprehensive Analysis of Combinatorial Pharmacological Treatments to Correct Nonsense Mutations in the CFTR Gene
by Arianna Venturini, Anna Borrelli, Ilaria Musante, Paolo Scudieri, Valeria Capurro, Mario Renda, Nicoletta Pedemonte and Luis J. V. Galietta
Int. J. Mol. Sci. 2021, 22(21), 11972; https://doi.org/10.3390/ijms222111972 - 4 Nov 2021
Cited by 22 | Viewed by 3303
Abstract
Cystic fibrosis (CF) is caused by loss of function of the CFTR chloride channel. A substantial number of CF patients carry nonsense mutations in the CFTR gene. These patients cannot directly benefit from pharmacological correctors and potentiators that have been developed for other [...] Read more.
Cystic fibrosis (CF) is caused by loss of function of the CFTR chloride channel. A substantial number of CF patients carry nonsense mutations in the CFTR gene. These patients cannot directly benefit from pharmacological correctors and potentiators that have been developed for other types of CFTR mutations. We evaluated the efficacy of combinations of drugs targeting at various levels the effects of nonsense mutations: SMG1i to protect CFTR mRNA from nonsense-mediated decay (NMD), G418 and ELX-02 for readthrough, VX-809 and VX-445 to promote protein maturation and function, PTI-428 to enhance CFTR protein synthesis. We found that the extent of rescue and sensitivity to the various agents is largely dependent on the type of mutation, with W1282X and R553X being the mutations most and least sensitive to pharmacological treatments, respectively. In particular, W1282X-CFTR was highly responsive to NMD suppression by SMG1i but also required treatment with VX-445 corrector to show function. In contrast, G542X-CFTR required treatment with readthrough agents and VX-809. Importantly, we never found cooperativity between the NMD inhibitor and readthrough compounds. Our results indicate that treatment of CF patients with nonsense mutations requires a precision medicine approach with the design of specific drug combinations for each mutation. Full article
(This article belongs to the Special Issue Therapeutic Approaches for Cystic Fibrosis 2.0)
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18 pages, 8518 KiB  
Article
Mucus Release and Airway Constriction by TMEM16A May Worsen Pathology in Inflammatory Lung Disease
by Raquel Centeio, Jiraporn Ousingsawat, Inês Cabrita, Rainer Schreiber, Khaoula Talbi, Roberta Benedetto, Tereza Doušová, Eric K. Verbeken, Kris De Boeck, Isaac Cohen and Karl Kunzelmann
Int. J. Mol. Sci. 2021, 22(15), 7852; https://doi.org/10.3390/ijms22157852 - 22 Jul 2021
Cited by 17 | Viewed by 2694
Abstract
Activation of the Ca2+ activated Cl− channel TMEM16A is proposed as a treatment in inflammatory airway disease. It is assumed that activation of TMEM16A will induce electrolyte secretion, and thus reduce airway mucus plugging and improve mucociliary clearance. A benefit of [...] Read more.
Activation of the Ca2+ activated Cl− channel TMEM16A is proposed as a treatment in inflammatory airway disease. It is assumed that activation of TMEM16A will induce electrolyte secretion, and thus reduce airway mucus plugging and improve mucociliary clearance. A benefit of activation of TMEM16A was shown in vitro and in studies in sheep, but others reported an increase in mucus production and airway contraction by activation of TMEM16A. We analyzed expression of TMEM16A in healthy and inflamed human and mouse airways and examined the consequences of activation or inhibition of TMEM16A in asthmatic mice. TMEM16A was found to be upregulated in the lungs of patients with asthma or cystic fibrosis, as well as in the airways of asthmatic mice. Activation or potentiation of TMEM16A by the compounds Eact or brevenal, respectively, induced acute mucus release from airway goblet cells and induced bronchoconstriction in mice in vivo. In contrast, niclosamide, an inhibitor of TMEM16A, blocked mucus production and mucus secretion in vivo and in vitro. Treatment of airway epithelial cells with niclosamide strongly inhibited expression of the essential transcription factor of Th2-dependent inflammation and goblet cell differentiation, SAM pointed domain-containing ETS-like factor (SPDEF). Activation of TMEM16A in people with inflammatory airway diseases is likely to induce mucus secretion along with airway constriction. In contrast, inhibitors of TMEM16A may suppress pulmonary Th2 inflammation, goblet cell metaplasia, mucus production, and bronchoconstriction, partially by inhibiting expression of SPDEF. Full article
(This article belongs to the Special Issue Therapeutic Approaches for Cystic Fibrosis 2.0)
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18 pages, 2727 KiB  
Article
Partial Rescue of F508del-CFTR Stability and Trafficking Defects by Double Corrector Treatment
by Valeria Capurro, Valeria Tomati, Elvira Sondo, Mario Renda, Anna Borrelli, Cristina Pastorino, Daniela Guidone, Arianna Venturini, Alessandro Giraudo, Sine Mandrup Bertozzi, Ilaria Musante, Fabio Bertozzi, Tiziano Bandiera, Federico Zara, Luis J. V. Galietta and Nicoletta Pedemonte
Int. J. Mol. Sci. 2021, 22(10), 5262; https://doi.org/10.3390/ijms22105262 - 17 May 2021
Cited by 44 | Viewed by 4485
Abstract
Deletion of phenylalanine at position 508 (F508del) in the CFTR chloride channel is the most frequent mutation in cystic fibrosis (CF) patients. F508del impairs the stability and folding of the CFTR protein, thus resulting in mistrafficking and premature degradation. F508del-CFTR defects can be [...] Read more.
Deletion of phenylalanine at position 508 (F508del) in the CFTR chloride channel is the most frequent mutation in cystic fibrosis (CF) patients. F508del impairs the stability and folding of the CFTR protein, thus resulting in mistrafficking and premature degradation. F508del-CFTR defects can be overcome with small molecules termed correctors. We investigated the efficacy and properties of VX-445, a newly developed corrector, which is one of the three active principles present in a drug (Trikafta®/Kaftrio®) recently approved for the treatment of CF patients with F508del mutation. We found that VX-445, particularly in combination with type I (VX-809, VX-661) and type II (corr-4a) correctors, elicits a large rescue of F508del-CFTR function. In particular, in primary bronchial epithelial cells of CF patients, the maximal rescue obtained with corrector combinations including VX-445 was close to 60–70% of CFTR function in non-CF cells. Despite this high efficacy, analysis of ubiquitylation, resistance to thermoaggregation, protein half-life, and subcellular localization revealed that corrector combinations did not fully normalize F508del-CFTR behavior. Our study indicates that it is still possible to further improve mutant CFTR rescue with the development of corrector combinations having maximal effects on mutant CFTR structural and functional properties. Full article
(This article belongs to the Special Issue Therapeutic Approaches for Cystic Fibrosis 2.0)
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16 pages, 2229 KiB  
Article
IRE1α Is a Therapeutic Target for Cystic Fibrosis Airway Inflammation
by Emily A. Hull-Ryde, John T. Minges, Mary E. B. Martino, Takafumi Kato, Jacqueline L. Norris-Drouin and Carla M. P. Ribeiro
Int. J. Mol. Sci. 2021, 22(6), 3063; https://doi.org/10.3390/ijms22063063 - 17 Mar 2021
Cited by 8 | Viewed by 2484
Abstract
New anti-inflammatory treatments are needed for CF airway disease. Studies have implicated the endoplasmic reticulum stress transducer inositol requiring enzyme 1α (IRE1α) in CF airway inflammation. The activation of IRE1α promotes activation of its cytoplasmic kinase and RNase, resulting in mRNA splicing of [...] Read more.
New anti-inflammatory treatments are needed for CF airway disease. Studies have implicated the endoplasmic reticulum stress transducer inositol requiring enzyme 1α (IRE1α) in CF airway inflammation. The activation of IRE1α promotes activation of its cytoplasmic kinase and RNase, resulting in mRNA splicing of X-box binding protein-1 (XBP-1s), a transcription factor required for cytokine production. We tested whether IRE1α kinase and RNase inhibition decreases cytokine production induced by the exposure of primary cultures of homozygous F508del CF human bronchial epithelia (HBE) to supernatant of mucopurulent material (SMM) from CF airways. We evaluated whether IRE1α expression is increased in freshly isolated and native CF HBE, and couples with increased XBP-1s levels. A FRET assay confirmed binding of the IRE1α kinase and RNase inhibitor, KIRA6, to the IRE1α kinase. F508del HBE cultures were exposed to SMM with or without KIRA6, and we evaluated the mRNA levels of XBP-1s, IL-6, and IL-8, and the secretion of IL-6 and IL-8. IRE1α mRNA levels were up-regulated in freshly isolated CF vs. normal HBE and coupled to increased XBP-1s mRNA levels. SMM increased XBP-1s, IL-6, and IL-8 mRNA levels and up-regulated IL-6 and IL-8 secretion, and KIRA6 blunted these responses in a dose-dependent manner. Moreover, a triple combination of CFTR modulators currently used in the clinic had no effect on SMM-increased XBP-1s levels coupled with increased cytokine production in presence or absence of KIRA6. These findings indicate that IRE1α mediates cytokine production in CF airways. Small molecule IRE1α kinase inhibitors that allosterically reduce RNase-dependent XBP-1s may represent a new therapeutic strategy for CF airway inflammation. Full article
(This article belongs to the Special Issue Therapeutic Approaches for Cystic Fibrosis 2.0)
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17 pages, 2729 KiB  
Article
CFTR Cooperative Cis-Regulatory Elements in Intestinal Cells
by Mégane Collobert, Ozvan Bocher, Anaïs Le Nabec, Emmanuelle Génin, Claude Férec and Stéphanie Moisan
Int. J. Mol. Sci. 2021, 22(5), 2599; https://doi.org/10.3390/ijms22052599 - 5 Mar 2021
Cited by 3 | Viewed by 2418
Abstract
About 8% of the human genome is covered with candidate cis-regulatory elements (cCREs). Disruptions of CREs, described as “cis-ruptions” have been identified as being involved in various genetic diseases. Thanks to the development of chromatin conformation study techniques, several long-range [...] Read more.
About 8% of the human genome is covered with candidate cis-regulatory elements (cCREs). Disruptions of CREs, described as “cis-ruptions” have been identified as being involved in various genetic diseases. Thanks to the development of chromatin conformation study techniques, several long-range cystic fibrosis transmembrane conductance regulator (CFTR) regulatory elements were identified, but the regulatory mechanisms of the CFTR gene have yet to be fully elucidated. The aim of this work is to improve our knowledge of the CFTR gene regulation, and to identity factors that could impact the CFTR gene expression, and potentially account for the variability of the clinical presentation of cystic fibrosis as well as CFTR-related disorders. Here, we apply the robust GWAS3D score to determine which of the CFTR introns could be involved in gene regulation. This approach highlights four particular CFTR introns of interest. Using reporter gene constructs in intestinal cells, we show that two new introns display strong cooperative effects in intestinal cells. Chromatin immunoprecipitation analyses further demonstrate fixation of transcription factors network. These results provide new insights into our understanding of the CFTR gene regulation and allow us to suggest a 3D CFTR locus structure in intestinal cells. A better understand of regulation mechanisms of the CFTR gene could elucidate cases of patients where the phenotype is not yet explained by the genotype. This would thus help in better diagnosis and therefore better management. These cis-acting regions may be a therapeutic challenge that could lead to the development of specific molecules capable of modulating gene expression in the future. Full article
(This article belongs to the Special Issue Therapeutic Approaches for Cystic Fibrosis 2.0)
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15 pages, 2768 KiB  
Article
Antibacterial Effects of Bicarbonate in Media Modified to Mimic Cystic Fibrosis Sputum
by Pongsiri Jaikumpun, Kasidid Ruksakiet, Balázs Stercz, Éva Pállinger, Martin Steward, Zsolt Lohinai, Orsolya Dobay and Ákos Zsembery
Int. J. Mol. Sci. 2020, 21(22), 8614; https://doi.org/10.3390/ijms21228614 - 16 Nov 2020
Cited by 9 | Viewed by 2748
Abstract
Cystic fibrosis (CF) is a hereditary disease caused by mutations in the gene encoding an epithelial anion channel. In CF, Cl− and HCO3− hyposecretion, together with mucin hypersecretion, leads to airway dehydration and production of viscous mucus. This habitat is [...] Read more.
Cystic fibrosis (CF) is a hereditary disease caused by mutations in the gene encoding an epithelial anion channel. In CF, Cl− and HCO3− hyposecretion, together with mucin hypersecretion, leads to airway dehydration and production of viscous mucus. This habitat is ideal for colonization by pathogenic bacteria. We have recently demonstrated that HCO3− inhibits the growth and biofilm formation of Pseudomonas aeruginosa and Staphylococcus aureus when tested in laboratory culture media. Using the same bacteria our aim was to investigate the effects of HCO3− in artificial sputum medium (ASM), whose composition resembles CF mucus. Control ASM containing no NaHCO3 was incubated in ambient air (pH 7.4 or 8.0). ASM containing NaHCO3 (25 and 100 mM) was incubated in 5% CO2 (pH 7.4 and 8.0, respectively). Viable P. aeruginosa and S. aureus cells were counted by colony-forming unit assay and flow cytometry after 6 h and 17 h of incubation. Biofilm formation was assessed after 48 h. The data show that HCO3− significantly decreased viable cell counts and biofilm formation in a concentration-dependent manner. These effects were due neither to extracellular alkalinization nor to altered osmolarity. These results show that HCO3− exerts direct antibacterial and antibiofilm effects on prevalent CF bacteria. Full article
(This article belongs to the Special Issue Therapeutic Approaches for Cystic Fibrosis 2.0)
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Review

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16 pages, 875 KiB  
Review
Nasal Epithelial Cell-Based Models for Individualized Study in Cystic Fibrosis
by Duncan E. Keegan and John J. Brewington
Int. J. Mol. Sci. 2021, 22(9), 4448; https://doi.org/10.3390/ijms22094448 - 24 Apr 2021
Cited by 15 | Viewed by 2814
Abstract
The emergence of highly effective CFTR modulator therapy has led to significant improvements in health care for most patients with cystic fibrosis (CF). For some, however, these therapies remain inaccessible due to the rarity of their individual CFTR variants, or due to a [...] Read more.
The emergence of highly effective CFTR modulator therapy has led to significant improvements in health care for most patients with cystic fibrosis (CF). For some, however, these therapies remain inaccessible due to the rarity of their individual CFTR variants, or due to a lack of biologic activity of the available therapies for certain variants. One proposed method of addressing this gap is the use of primary human cell-based models, which allow preclinical therapeutic testing and physiologic assessment of relevant tissue at the individual level. Nasal cells represent one such tissue source and have emerged as a powerful model for individual disease study. The ex vivo culture of nasal cells has evolved over time, and modern nasal cell models are beginning to be utilized to predict patient outcomes. This review will discuss both historical and current state-of-the art use of nasal cells for study in CF, with a particular focus on the use of such models to inform personalized patient care. Full article
(This article belongs to the Special Issue Therapeutic Approaches for Cystic Fibrosis 2.0)
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15 pages, 1826 KiB  
Review
Small Hsps as Therapeutic Targets of Cystic Fibrosis Transmembrane Conductance Regulator Protein
by Stéphanie Simon, Abdel Aissat, Fanny Degrugillier, Benjamin Simonneau, Pascale Fanen and André-Patrick Arrigo
Int. J. Mol. Sci. 2021, 22(8), 4252; https://doi.org/10.3390/ijms22084252 - 20 Apr 2021
Cited by 2 | Viewed by 3074
Abstract
Human small heat shock proteins are molecular chaperones that regulate fundamental cellular processes in normal and pathological cells. Here, we have reviewed the role played by HspB1, HspB4 and HspB5 in the context of Cystic Fibrosis (CF), a severe monogenic autosomal recessive disease [...] Read more.
Human small heat shock proteins are molecular chaperones that regulate fundamental cellular processes in normal and pathological cells. Here, we have reviewed the role played by HspB1, HspB4 and HspB5 in the context of Cystic Fibrosis (CF), a severe monogenic autosomal recessive disease linked to mutations in Cystic Fibrosis Transmembrane conductance Regulator protein (CFTR) some of which trigger its misfolding and rapid degradation, particularly the most frequent one, F508del-CFTR. While HspB1 and HspB4 favor the degradation of CFTR mutants, HspB5 and particularly one of its phosphorylated forms positively enhance the transport at the plasma membrane, stability and function of the CFTR mutant. Moreover, HspB5 molecules stimulate the cellular efficiency of currently used CF therapeutic molecules. Different strategies are suggested to modulate the level of expression or the activity of these small heat shock proteins in view of potential in vivo therapeutic approaches. We then conclude with other small heat shock proteins that should be tested or further studied to improve our knowledge of CFTR processing. Full article
(This article belongs to the Special Issue Therapeutic Approaches for Cystic Fibrosis 2.0)
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24 pages, 2238 KiB  
Review
Airway Surface Liquid pH Regulation in Airway Epithelium Current Understandings and Gaps in Knowledge
by Miroslaw Zajac, Elise Dreano, Aurelie Edwards, Gabrielle Planelles and Isabelle Sermet-Gaudelus
Int. J. Mol. Sci. 2021, 22(7), 3384; https://doi.org/10.3390/ijms22073384 - 25 Mar 2021
Cited by 49 | Viewed by 5671
Abstract
Knowledge on the mechanisms of acid and base secretion in airways has progressed recently. The aim of this review is to summarize the known mechanisms of airway surface liquid (ASL) pH regulation and their implication in lung diseases. Normal ASL is slightly acidic [...] Read more.
Knowledge on the mechanisms of acid and base secretion in airways has progressed recently. The aim of this review is to summarize the known mechanisms of airway surface liquid (ASL) pH regulation and their implication in lung diseases. Normal ASL is slightly acidic relative to the interstitium, and defects in ASL pH regulation are associated with various respiratory diseases, such as cystic fibrosis. Basolateral bicarbonate (HCO3−) entry occurs via the electrogenic, coupled transport of sodium (Na+) and HCO3−, and, together with carbonic anhydrase enzymatic activity, provides HCO3− for apical secretion. The latter mainly involves CFTR, the apical chloride/bicarbonate exchanger pendrin and paracellular transport. Proton (H+) secretion into ASL is crucial to maintain its relative acidity compared to the blood. This is enabled by H+ apical secretion, mainly involving H+/K+ ATPase and vacuolar H+-ATPase that carry H+ against the electrochemical potential gradient. Paracellular HCO3− transport, the direction of which depends on the ASL pH value, acts as an ASL protective buffering mechanism. How the transepithelial transport of H+ and HCO3− is coordinated to tightly regulate ASL pH remains poorly understood, and should be the focus of new studies. Full article
(This article belongs to the Special Issue Therapeutic Approaches for Cystic Fibrosis 2.0)
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22 pages, 261 KiB  
Review
Current Treatment Options for Cystic Fibrosis-Related Liver Disease
by Katharina Staufer
Int. J. Mol. Sci. 2020, 21(22), 8586; https://doi.org/10.3390/ijms21228586 - 14 Nov 2020
Cited by 27 | Viewed by 3997
Abstract
Cystic Fibrosis-related liver disease (CFLD) has become a leading cause of morbidity and mortality in patients with Cystic Fibrosis (CF), and affects children and adults. The understanding of the pathogenesis of CFLD is key in order to develop efficacious treatments. However, it remains [...] Read more.
Cystic Fibrosis-related liver disease (CFLD) has become a leading cause of morbidity and mortality in patients with Cystic Fibrosis (CF), and affects children and adults. The understanding of the pathogenesis of CFLD is key in order to develop efficacious treatments. However, it remains complex, and has not been clarified to the last. The search for a drug might be additionally complicated due to the diverse clinical picture and lack of a unified definition of CFLD. Although ursodeoxycholic acid has been used for decades, its efficacy in CFLD is controversial, and the potential of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) modulators and targeted gene therapy in CFLD needs to be defined in the near future. This review focuses on the current knowledge on treatment strategies for CFLD based on pathomechanistic viewpoints. Full article
(This article belongs to the Special Issue Therapeutic Approaches for Cystic Fibrosis 2.0)
23 pages, 657 KiB  
Review
From Ivacaftor to Triple Combination: A Systematic Review of Efficacy and Safety of CFTR Modulators in People with Cystic Fibrosis
by Andrea Gramegna, Martina Contarini, Stefano Aliberti, Rosaria Casciaro, Francesco Blasi and Carlo Castellani
Int. J. Mol. Sci. 2020, 21(16), 5882; https://doi.org/10.3390/ijms21165882 - 16 Aug 2020
Cited by 51 | Viewed by 5232
Abstract
Over the last years CFTR (cystic fibrosis transmembrane conductance regulator) modulators have shown the ability to improve relevant clinical outcomes in patients with cystic fibrosis (CF). This review aims at a systematic research of the current evidence on efficacy and tolerability of CFTR [...] Read more.
Over the last years CFTR (cystic fibrosis transmembrane conductance regulator) modulators have shown the ability to improve relevant clinical outcomes in patients with cystic fibrosis (CF). This review aims at a systematic research of the current evidence on efficacy and tolerability of CFTR modulators for different genetic subsets of patients with CF. Two investigators independently performed the search on PubMed and included phase 2 and 3 clinical trials published in the study period 1 January 2005–31 January 2020. A final pool of 23 papers was included in the systematic review for a total of 4219 patients. For each paper data of interest were extracted and reported in table. In terms of lung function, patients who had the most beneficial effects from CFTR modulation were those patients with one gating mutation receiving IVA (ivacaftor) and patients with p.Phe508del mutation, both homozygous and heterozygous, receiving ELX/TEZ/IVA (elexacaftor/tezacaftor/ivacaftor) had the most relevant beneficial effects in term of lung function, pulmonary exacerbation decrease, and symptom improvement. CFTR modulators showed an overall favorable safety profile. Next steps should aim to systematize our comprehension of scientific data of efficacy and safety coming from real life observational studies. Full article
(This article belongs to the Special Issue Therapeutic Approaches for Cystic Fibrosis 2.0)
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19 pages, 1851 KiB  
Review
Proteomics and Metabolomics for Cystic Fibrosis Research
by Nara Liessi, Nicoletta Pedemonte, Andrea Armirotti and Clarissa Braccia
Int. J. Mol. Sci. 2020, 21(15), 5439; https://doi.org/10.3390/ijms21155439 - 30 Jul 2020
Cited by 17 | Viewed by 4783
Abstract
The aim of this review article is to introduce the reader to the state-of-the-art of the contribution that proteomics and metabolomics sciences are currently providing for cystic fibrosis (CF) research: from the understanding of cystic fibrosis transmembrane conductance regulator (CFTR) biology to biomarker [...] Read more.
The aim of this review article is to introduce the reader to the state-of-the-art of the contribution that proteomics and metabolomics sciences are currently providing for cystic fibrosis (CF) research: from the understanding of cystic fibrosis transmembrane conductance regulator (CFTR) biology to biomarker discovery for CF diagnosis. Our work particularly focuses on CFTR post-translational modifications and their role in cellular trafficking as well as on studies that allowed the identification of CFTR molecular interactors. We also show how metabolomics is currently helping biomarker discovery in CF. The most recent advances in these fields are covered by this review, as well as some considerations on possible future scenarios for new applications. Full article
(This article belongs to the Special Issue Therapeutic Approaches for Cystic Fibrosis 2.0)
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20 pages, 1515 KiB  
Review
Cell-Based Therapeutic Approaches for Cystic Fibrosis
by Pascal Duchesneau, Thomas K. Waddell and Golnaz Karoubi
Int. J. Mol. Sci. 2020, 21(15), 5219; https://doi.org/10.3390/ijms21155219 - 23 Jul 2020
Cited by 13 | Viewed by 6400
Abstract
Cystic Fibrosis (CF) is a chronic autosomal recessive disease caused by defects in the cystic fibrosis transmembrane conductance regulator gene (CFTR). Cystic Fibrosis affects multiple organs but progressive remodeling of the airways, mucus accumulation, and chronic inflammation in the lung, result [...] Read more.
Cystic Fibrosis (CF) is a chronic autosomal recessive disease caused by defects in the cystic fibrosis transmembrane conductance regulator gene (CFTR). Cystic Fibrosis affects multiple organs but progressive remodeling of the airways, mucus accumulation, and chronic inflammation in the lung, result in lung disease as the major cause of morbidity and mortality. While advances in management of CF symptoms have increased the life expectancy of this devastating disease, and there is tremendous excitement about the potential of new agents targeting the CFTR molecule itself, there is still no curative treatment. With the recent advances in the identification of endogenous airway progenitor cells and in directed differentiation of pluripotent cell sources, cell-based therapeutic approaches for CF have become a plausible treatment method with the potential to ultimately cure the disease. In this review, we highlight the current state of cell therapy in the CF field focusing on the relevant autologous and allogeneic cell populations under investigation and the challenges associated with their use. In addition, we present advances in induced pluripotent stem (iPS) cell approaches and emerging new genetic engineering methods, which have the capacity to overcome the current limitations hindering cell therapy approaches. Full article
(This article belongs to the Special Issue Therapeutic Approaches for Cystic Fibrosis 2.0)
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Other

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8 pages, 268 KiB  
Perspective
Is the ENaC Dysregulation in CF an Effect of Protein-Lipid Interaction in the Membranes?
by Birgitta Strandvik
Int. J. Mol. Sci. 2021, 22(5), 2739; https://doi.org/10.3390/ijms22052739 - 8 Mar 2021
Cited by 7 | Viewed by 1798
Abstract
While approximately 2000 mutations have been discovered in the gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR), only a small amount (about 10%) is associated with clinical cystic fibrosis (CF) disease. The discovery of the association between CFTR and the hyperactive [...] Read more.
While approximately 2000 mutations have been discovered in the gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR), only a small amount (about 10%) is associated with clinical cystic fibrosis (CF) disease. The discovery of the association between CFTR and the hyperactive epithelial sodium channel (ENaC) has raised the question of the influence of ENaC on the clinical CF phenotype. ENaC disturbance contributes to the pathological secretion, and overexpression of one ENaC subunit, the β-unit, can give a CF-like phenotype in mice with normal acting CFTR. The development of ENaC channel modulators is now in progress. Both CFTR and ENaC are located in the cell membrane and are influenced by its lipid configuration. Recent studies have emphasized the importance of the interaction of lipids and these proteins in the membranes. Linoleic acid deficiency is the most prevailing lipid abnormality in CF, and linoleic acid is an important constituent of membranes. The influence on sodium excretion by linoleic acid supplementation indicates that lipid-protein interaction is of importance for the clinical pathophysiology in CF. Further studies of this association can imply a simple clinical adjuvant in CF therapy. Full article
(This article belongs to the Special Issue Therapeutic Approaches for Cystic Fibrosis 2.0)
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