Cystic Fibrosis

Topic Information

Dear Colleagues,

Cystic fibrosis (CF) is caused by loss-of-function mutations in the CFTR gene, which encodes for the CFTR chloride/bicarbonate channel. These mutations may have pleiotropic effects on the CFTR protein, including processing disruption of, and stability at, the plasma membrane (PM) and chloride channel activity. Over the last decade, novel drugs, called modulators, have been developed to rescue the basic defect caused by specific mutations. Because of this complex disease etiology, a combination of CFTR modulators is generally required to rescue the trafficking and functional defects of disease-associated CFTR variants. Due to these disease-modifying treatments, unprecedented clinical results have been achieved in people with eligible CF genotypes. However, real-world data show that there are still a considerable number of people with CF, with covered mutations, who may benefit from alternative modulator therapies. These unconventional candidates may address heterogeneity in patient response, as well as promoting increased market competition and providing increased global access. Moreover, we must consider that CF is characterized by remarkable allelic heterogeneity. Many patients cannot yet benefit from these treatments, as in the cases of patients carrying rare mutations still missing an approved treatment and unable to be included in clinical trials due to the rarity of their mutations. Indeed, traditional randomized trials would require sample sizes that exceed the entire eligible population. Theratyping procedures by means of in vitro predictive models can facilitate personalized medicine approaches to move therapy forward for all people with CF. Despite these efforts, some CF variants will remain difficult to rescue by “classical” CFTR modulators, and there is the need to develop gene-based therapies able to replace or edit the CFTR gene. Alternative approaches focused on the restoration of epithelial homeostasis by targeting proteins other than CFTR could also constitute mutation-agnostic therapies useful for all the patients regardless their genotypes. This topic on "Cystic Fibrosis" aims to gather reviews and original articles focused on novel, promising therapeutic approaches for this devastating disease at basic, translational and clinical levels, to provide expert insights and perspectives on advances in the field.

Dr. Nicoletta Pedemonte
Dr. Miqueias Lopes Pacheco
Dr. Vito Terlizzi
Dr. Paolo Scudieri
Dr. Fabio Bertozzi
Topic Editors

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Participating Journals

Journal Name	Impact Factor	CiteScore	Launched Year	First Decision (median)	APC
Cells cells	6.0	9.0	2012	16.6 Days	CHF 2700
International Journal of Molecular Sciences ijms	5.6	7.8	2000	16.3 Days	CHF 2900
Journal of Clinical Medicine jcm	3.9	5.4	2012	17.9 Days	CHF 2600
Journal of Personalized Medicine jpm	3.4	2.6	2011	17.8 Days	CHF 2600
Pharmaceutics pharmaceutics	5.4	6.9	2009	14.2 Days	CHF 2900

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16 pages, 493 KiB  

Open AccessArticle

Parents’ Knowledge of the Impact of Cystic Fibrosis on the Quality of Life of Children and Adolescents Suffering from This Disease as an Element of Patient Safety

by Grażyna Dykowska, Ewa Śmigrocka, Urszula Borawska-Kowalczyk, Dorota Sands, Zofia Sienkiewicz, Anna Leńczuk-Gruba, Damian Gorczyca and Mariola Głowacka

J. Clin. Med. 2023, 12(16), 5214; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm12165214 - 10 Aug 2023

Viewed by 906

Abstract

Parental perspective on the health, safety, and quality of life in children and adolescents with cystic fibrosis (CF). Aim of the study: Assessment of the impact of a chronic disease such as cystic fibrosis (CF) on the quality of life and safety of [...] Read more.

Parental perspective on the health, safety, and quality of life in children and adolescents with cystic fibrosis (CF). Aim of the study: Assessment of the impact of a chronic disease such as cystic fibrosis (CF) on the quality of life and safety of children and adolescents as perceived by parents/caretakers. Methods: The study was conducted at the Department of Lung Diseases of the Institute of Mother and Child, a branch of the Cystic Fibrosis Centre Children of Warsaw SZPZOZ in Dziekanów Leśny, the largest pediatric CF center in Poland, and in the Rodzinamuko group on Facebook. A total of 139 parents participated in the study. The study was conducted using the diagnostic survey method with the use of the Kid- & Kiddo-KINDLR questionnaire for examining the quality of life of children and adolescents and a demographic questionnaire. Results: The perception of cystic fibrosis (CF) as a chronic disease varies based on parental residence and professional status. The well-being of children and adolescents with CF is tied to their parents’ employment, particularly regarding schooling. Social interactions are influenced by the level of parental education. The quality of life in children and adolescents with CF is age-dependent, with younger children exhibiting higher quality of life. This age–quality of life relationship extends to physical well-being, emotional well-being, and school-related aspects. Furthermore, the emotional dimension of quality of life is affected by the child’s age at the time of diagnosis. Conclusions: The Kid- & Kiddo-KINDLR QoL Questionnaire for children with cystic fibrosis is a good tool to measure parental knowledge. The study shows the need for the whole family to understand and be aware of the impact of CF on family life. Parents may be tired or may misunderstand or miscommunicate the medical team’s instructions, which may affect both family life and patient safety. To ensure patient safety, parents should work with healthcare professionals at hospitals or clinics but also at home. They should also account for the family as a whole, not just for the problems of the child with CF. Full article

(This article belongs to the Topic Cystic Fibrosis)

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14 pages, 542 KiB  

Open AccessArticle

Pulmonary Function Tests in the Evaluation of Early Lung Disease in Cystic Fibrosis

by Katarzyna Walicka-Serzysko, Magdalena Postek, Urszula Borawska-Kowalczyk, Justyna Milczewska and Dorota Sands

J. Clin. Med. 2023, 12(14), 4735; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm12144735 - 17 Jul 2023

Cited by 1 | Viewed by 1133

Abstract

Background: Properly evaluating respiratory system dysfunction is essential in children with cystic fibrosis (CF). This prospective study aimed to assess the course of early lung disease based on multiple breath nitrogen washout (MBNW), impulse oscillometry (IOS), and conventional techniques, such as spirometry and [...] Read more.

Background: Properly evaluating respiratory system dysfunction is essential in children with cystic fibrosis (CF). This prospective study aimed to assess the course of early lung disease based on multiple breath nitrogen washout (MBNW), impulse oscillometry (IOS), and conventional techniques, such as spirometry and body plethysmography. Methods: Over a 2 year recruitment period, subjects with CF aged 7–18 performed pulmonary function tests (PFTs). Moreover, the nutritional and microbiological status, frequency of pulmonary exacerbations (PExs), and patients’ health-related quality of life (HRQoL) were assessed. Results: The mean age of the children (n = 69) was 14.09 ± 3.26 years; F/M 37/32. Spirometry-based diagnoses of normal lung function (forced expiratory volume in 1 s, FEV₁ ≥ 90%pred), mild (FEV₁ 70–89%pred) and moderate (FEV₁ 40–69%pred) lung diseases were established in 34 (49.3%), 25 (36.2%), and 10 (14.5%) patients, respectively. An elevated lung clearance index (LCI > 6.98) was observed in 85% of the subjects with normal FEV₁. The presence of Pseudomonas aeruginosa infection (n = 16) and the number of PExs treated with IV antibiotics were associated with significantly worse PFT results. Conclusions: MBNW and IOS are more helpful tools than conventional techniques in assessing early lung disease in CF. LCI is a more useful parameter for detecting functional abnormalities than FEV₁ in school-age children. Full article

(This article belongs to the Topic Cystic Fibrosis)

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20 pages, 5746 KiB  

Open AccessArticle

Molecular and Functional Characteristics of Airway Epithelium under Chronic Hypoxia

by Sharon L. Wong, Egi Kardia, Abhishek Vijayan, Bala Umashankar, Elvis Pandzic, Ling Zhong, Adam Jaffe and Shafagh A. Waters

Int. J. Mol. Sci. 2023, 24(7), 6475; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24076475 - 30 Mar 2023

Viewed by 2114

Abstract

Localized and chronic hypoxia of airway mucosa is a common feature of progressive respiratory diseases, including cystic fibrosis (CF). However, the impact of prolonged hypoxia on airway stem cell function and differentiated epithelium is not well elucidated. Acute hypoxia alters the transcription and [...] Read more.

Localized and chronic hypoxia of airway mucosa is a common feature of progressive respiratory diseases, including cystic fibrosis (CF). However, the impact of prolonged hypoxia on airway stem cell function and differentiated epithelium is not well elucidated. Acute hypoxia alters the transcription and translation of many genes, including the CF transmembrane conductance regulator (CFTR). CFTR-targeted therapies (modulators) have not been investigated in vitro under chronic hypoxic conditions found in CF airways in vivo. Nasal epithelial cells (hNECs) derived from eight CF and three non-CF participants were expanded and differentiated at the air–liquid interface (26–30 days) at ambient and 2% oxygen tension (hypoxia). Morphology, global proteomics (LC-MS/MS) and function (barrier integrity, cilia motility and ion transport) of basal stem cells and differentiated cultures were assessed. hNECs expanded at chronic hypoxia, demonstrating epithelial cobblestone morphology and a similar proliferation rate to hNECs expanded at normoxia. Hypoxia-inducible proteins and pathways in stem cells and differentiated cultures were identified. Despite the stem cells’ plasticity and adaptation to chronic hypoxia, the differentiated epithelium was significantly thinner with reduced barrier integrity. Stem cell lineage commitment shifted to a more secretory epithelial phenotype. Motile cilia abundance, length, beat frequency and coordination were significantly negatively modulated. Chronic hypoxia reduces the activity of epithelial sodium and CFTR ion channels. CFTR modulator drug response was diminished. Our findings shed light on the molecular pathophysiology of hypoxia and its implications in CF. Targeting hypoxia can be a strategy to augment mucosal function and may provide a means to enhance the efficacy of CFTR modulators. Full article

(This article belongs to the Topic Cystic Fibrosis)

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24 pages, 6897 KiB  

Open AccessArticle

Rescue of Rare CFTR Trafficking Mutants Highlights a Structural Location-Dependent Pattern for Correction

by Sónia Zacarias, Marta S. P. Batista, Sofia S. Ramalho, Bruno L. Victor and Carlos M. Farinha

Int. J. Mol. Sci. 2023, 24(4), 3211; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24043211 - 06 Feb 2023

Cited by 3 | Viewed by 2378

Abstract

Cystic Fibrosis (CF) is a genetic disease caused by mutations in the gene encoding the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) channel. Currently, more than 2100 variants have been identified in the gene, with a large number being very rare. The approval of [...] Read more.

Cystic Fibrosis (CF) is a genetic disease caused by mutations in the gene encoding the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) channel. Currently, more than 2100 variants have been identified in the gene, with a large number being very rare. The approval of modulators that act on mutant CFTR protein, correcting its molecular defect and thus alleviating the burden of the disease, revolutionized the field of CF. However, these drugs do not apply to all patients with CF, especially those with rare mutations—for which there is a lack of knowledge on the molecular mechanisms of the disease and the response to modulators. In this work, we evaluated the impact of several rare putative class II mutations on the expression, processing, and response of CFTR to modulators. Novel cell models consisting of bronchial epithelial cell lines expressing CFTR with 14 rare variants were created. The variants studied are localized at Transmembrane Domain 1 (TMD1) or very close to the signature motif of Nucleotide Binding Domain 1 (NBD1). Our data show that all mutations analyzed significantly decrease CFTR processing and while TMD1 mutations respond to modulators, those localized in NBD1 do not. Molecular modeling calculations confirm that the mutations in NBD1 induce greater destabilization of CFTR structure than those in TMD1. Furthermore, the structural proximity of TMD1 mutants to the reported binding site of CFTR modulators such as VX-809 and VX-661, make them more efficient in stabilizing the CFTR mutants analyzed. Overall, our data suggest a pattern for mutation location and impact in response to modulators that correlates with the global effect of the mutations on CFTR structure. Full article

(This article belongs to the Topic Cystic Fibrosis)

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20 pages, 4465 KiB  

Open AccessArticle

Gain- and Loss-of-Function CFTR Alleles Are Associated with COVID-19 Clinical Outcomes

by Margherita Baldassarri, Kristina Zguro, Valeria Tomati, Cristina Pastorino, Francesca Fava, Susanna Croci, Mirella Bruttini, Nicola Picchiotti, Simone Furini, GEN-COVID Multicenter Study, Nicoletta Pedemonte, Chiara Gabbi, Alessandra Renieri and Chiara Fallerini

Cells 2022, 11(24), 4096; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11244096 - 16 Dec 2022

Cited by 3 | Viewed by 2198

Abstract

Carriers of single pathogenic variants of the CFTR (cystic fibrosis transmembrane conductance regulator) gene have a higher risk of severe COVID-19 and 14-day death. The machine learning post-Mendelian model pinpointed CFTR as a bidirectional modulator of COVID-19 outcomes. Here, we demonstrate that the [...] Read more.

Carriers of single pathogenic variants of the CFTR (cystic fibrosis transmembrane conductance regulator) gene have a higher risk of severe COVID-19 and 14-day death. The machine learning post-Mendelian model pinpointed CFTR as a bidirectional modulator of COVID-19 outcomes. Here, we demonstrate that the rare complex allele [G576V;R668C] is associated with a milder disease via a gain-of-function mechanism. Conversely, CFTR ultra-rare alleles with reduced function are associated with disease severity either alone (dominant disorder) or with another hypomorphic allele in the second chromosome (recessive disorder) with a global residual CFTR activity between 50 to 91%. Furthermore, we characterized novel CFTR complex alleles, including [A238V;F508del], [R74W;D1270N;V201M], [I1027T;F508del], [I506V;D1168G], and simple alleles, including R347C, F1052V, Y625N, I328V, K68E, A309D, A252T, G542*, V562I, R1066H, I506V, I807M, which lead to a reduced CFTR function and thus, to more severe COVID-19. In conclusion, CFTR genetic analysis is an important tool in identifying patients at risk of severe COVID-19. Full article

(This article belongs to the Topic Cystic Fibrosis)

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30 pages, 1710 KiB  

Open AccessArticle

Redefining Hypo- and Hyper-Responding Phenotypes of CFTR Mutants for Understanding and Therapy

by Tamara Hillenaar, Jeffrey Beekman, Peter van der Sluijs and Ineke Braakman

Int. J. Mol. Sci. 2022, 23(23), 15170; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232315170 - 02 Dec 2022

Cited by 2 | Viewed by 1628

Abstract

Mutations in CFTR cause misfolding and decreased or absent ion-channel function, resulting in the disease Cystic Fibrosis. Fortunately, a triple-modulator combination therapy (Trikafta) has been FDA-approved for 178 mutations, including all patients who have F508del on one allele. That so many CFTR mutants [...] Read more.

Mutations in CFTR cause misfolding and decreased or absent ion-channel function, resulting in the disease Cystic Fibrosis. Fortunately, a triple-modulator combination therapy (Trikafta) has been FDA-approved for 178 mutations, including all patients who have F508del on one allele. That so many CFTR mutants respond well to modulators developed for a single mutation is due to the nature of the folding process of this multidomain protein. We have addressed the question ‘What characterizes the exceptions: the mutants that functionally respond either not or extremely well’. A functional response is the product of the number of CFTR molecules on the cell surface, open probability, and conductivity of the CFTR chloride channel. By combining biosynthetic radiolabeling with protease-susceptibility assays, we have followed CF-causing mutants during the early and late stages of folding in the presence and absence of modulators. Most CFTR mutants showed typical biochemical responses for each modulator, such as a TMD1 conformational change or an increase in (cell-surface) stability, regardless of a functional response. These modulators thus should still be considered for hypo-responder genotypes. Understanding both biochemical and functional phenotypes of outlier mutations will boost our insights into CFTR folding and misfolding, and lead to improved therapeutic strategies. Full article

(This article belongs to the Topic Cystic Fibrosis)

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12 pages, 632 KiB  

Open AccessReview

Modifier Factors of Cystic Fibrosis Phenotypes: A Focus on Modifier Genes

by Julie Mésinèle, Manon Ruffin, Loïc Guillot and Harriet Corvol

Int. J. Mol. Sci. 2022, 23(22), 14205; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232214205 - 17 Nov 2022

Cited by 7 | Viewed by 3027

Abstract

Although cystic fibrosis (CF) is recognized as a monogenic disease, due to variants within the CFTR (Cystic Fibrosis Transmembrane Regulator) gene, an extreme clinical heterogeneity is described among people with CF (pwCF). Apart from the exocrine pancreatic status, most studies agree [...] Read more.

Although cystic fibrosis (CF) is recognized as a monogenic disease, due to variants within the CFTR (Cystic Fibrosis Transmembrane Regulator) gene, an extreme clinical heterogeneity is described among people with CF (pwCF). Apart from the exocrine pancreatic status, most studies agree that there is little association between CFTR variants and disease phenotypes. Environmental factors have been shown to contribute to this heterogeneity, accounting for almost 50% of the variability of the lung function of pwCF. Nevertheless, pwCF with similar CFTR variants and sharing the same environment (such as in siblings) may have highly variable clinical manifestations not explained by CFTR variants, and only partly explained by environmental factors. It is recognized that genetic variants located outside the CFTR locus, named “modifier genes”, influence the clinical expression of the disease. This short review discusses the latest studies that have described modifier factors associated with the various CF phenotypes as well as the response to the recent CFTR modulator therapies. Full article

(This article belongs to the Topic Cystic Fibrosis)

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8 pages, 1449 KiB  

Open AccessCommunication

Elexacaftor/Tezacaftor/Ivacaftor Accelerates Wound Repair in Cystic Fibrosis Airway Epithelium

by Onofrio Laselva and Massimo Conese

J. Pers. Med. 2022, 12(10), 1577; https://0-doi-org.brum.beds.ac.uk/10.3390/jpm12101577 - 25 Sep 2022

Cited by 3 | Viewed by 1491

Abstract

Background: Cystic fibrosis (CF) airway epithelium shows alterations in repair following damage. In vitro studies showed that lumacaftor/ivacaftor (Orkambi) may favor airway epithelial integrity in CF patients. Our aim was to evaluate the effect of the novel triple combination elexacaftor/tezacaftor/ivacaftor (ETI) on wound [...] Read more.

Background: Cystic fibrosis (CF) airway epithelium shows alterations in repair following damage. In vitro studies showed that lumacaftor/ivacaftor (Orkambi) may favor airway epithelial integrity in CF patients. Our aim was to evaluate the effect of the novel triple combination elexacaftor/tezacaftor/ivacaftor (ETI) on wound repair in CF airway epithelial cells. Methods: A tip-based scratch assay was employed to study wound repair in monolayers of CFBE14o- cells overexpressing the F508del mutation. ETI was added during wound repair. Results: ETI efficiently rescued CFTR F508del maturation and activity, accelerated wound closure and increased wound healing rates of the injured CF cell monolayers. Conclusions: The triple corrector/potentiator combination ETI shows promise in ameliorating wound healing of the airway epithelium in F508del patients. Full article

(This article belongs to the Topic Cystic Fibrosis)

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25 pages, 4386 KiB  

Open AccessArticle

CFTR Rescue by Lumacaftor (VX-809) Induces an Extensive Reorganization of Mitochondria in the Cystic Fibrosis Bronchial Epithelium

by Clarissa Braccia, Josie A. Christopher, Oliver M. Crook, Lisa M. Breckels, Rayner M. L. Queiroz, Nara Liessi, Valeria Tomati, Valeria Capurro, Tiziano Bandiera, Simona Baldassari, Nicoletta Pedemonte, Kathryn S. Lilley and Andrea Armirotti

Cells 2022, 11(12), 1938; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11121938 - 16 Jun 2022

Cited by 4 | Viewed by 2617

Abstract

Background: Cystic Fibrosis (CF) is a genetic disorder affecting around 1 in every 3000 newborns. In the most common mutation, F508del, the defective anion channel, CFTR, is prevented from reaching the plasma membrane (PM) by the quality check control of the cell. Little [...] Read more.

Background: Cystic Fibrosis (CF) is a genetic disorder affecting around 1 in every 3000 newborns. In the most common mutation, F508del, the defective anion channel, CFTR, is prevented from reaching the plasma membrane (PM) by the quality check control of the cell. Little is known about how CFTR pharmacological rescue impacts the cell proteome. Methods: We used high-resolution mass spectrometry, differential ultracentrifugation, machine learning and bioinformatics to investigate both changes in the expression and localization of the human bronchial epithelium CF model (F508del-CFTR CFBE41o-) proteome following treatment with VX-809 (Lumacaftor), a drug able to improve the trafficking of CFTR. Results: The data suggested no stark changes in protein expression, yet subtle localization changes of proteins of the mitochondria and peroxisomes were detected. We then used high-content confocal microscopy to further investigate the morphological and compositional changes of peroxisomes and mitochondria under these conditions, as well as in patient-derived primary cells. We profiled several thousand proteins and we determined the subcellular localization data for around 5000 of them using the LOPIT-DC spatial proteomics protocol. Conclusions: We observed that treatment with VX-809 induces extensive structural and functional remodelling of mitochondria and peroxisomes that resemble the phenotype of healthy cells. Our data suggest additional rescue mechanisms of VX-809 beyond the correction of aberrant folding of F508del-CFTR and subsequent trafficking to the PM. Full article

(This article belongs to the Topic Cystic Fibrosis)

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16 pages, 2497 KiB  

Open AccessArticle

Liposome-Encapsulated Tobramycin and IDR-1018 Peptide Mediated Biofilm Disruption and Enhanced Antimicrobial Activity against Pseudomonas aeruginosa

by Nouf M. Alzahrani, Rayan Y. Booq, Ahmad M. Aldossary, Abrar A. Bakr, Fahad A. Almughem, Ahmed J. Alfahad, Wijdan K. Alsharif, Somayah J. Jarallah, Waleed S. Alharbi, Samar A. Alsudir, Essam J. Alyamani, Essam A. Tawfik and Abdullah A. Alshehri

Pharmaceutics 2022, 14(5), 960; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14050960 - 28 Apr 2022

Cited by 13 | Viewed by 2977

Abstract

The inadequate eradication of pulmonary infections and chronic inflammation are significant complications in cystic fibrosis (CF) patients, who usually suffer from persistent and frequent lung infections caused by several pathogens, particularly Pseudomonas aeruginosa (P. aeruginosa). The ability of pathogenic microbes to [...] Read more.

The inadequate eradication of pulmonary infections and chronic inflammation are significant complications in cystic fibrosis (CF) patients, who usually suffer from persistent and frequent lung infections caused by several pathogens, particularly Pseudomonas aeruginosa (P. aeruginosa). The ability of pathogenic microbes to protect themselves from biofilms leads to the development of an innate immune response and antibiotic resistance. In the present work, a reference bacterial strain of P. aeruginosa (PA01) and a multidrug-resistant isolate (MDR 7067) were used to explore the microbial susceptibility to three antibiotics (ceftazidime, imipenem, and tobramycin) and an anti-biofilm peptide (IDR-1018 peptide) using the minimum inhibition concentration (MIC). The most effective antibiotic was then encapsulated into liposomal nanoparticles and the IDR-1018 peptide with antibacterial activity, and the ability to disrupt the produced biofilm against PA01 and MDR 7067 was assessed. The MIC evaluation of the tobramycin antibacterial activity showed an insignificant effect on the liposomes loaded with tobramycin and liposomes encapsulating tobramycin and IDR-1018 against both P. aeruginosa strains to free tobramycin. Nevertheless, the biofilm formation was significantly reduced (p < 0.05) at concentrations of ≥4 μg/mL and ≤32 μg/mL for PA01 and ≤32 μg/mL for MDR 7067 when loading tobramycin into liposomes, with or without the anti-biofilm peptide compared to the free antibiotic, empty liposomes, and IDR-1018-loaded liposomes. A tobramycin concentration of ≤256 µg/mL was safe when exposed to a lung carcinoma cell line upon its encapsulation into the liposomal formulation. Tobramycin-loaded liposomes could be a potential candidate for treating lung-infected animal models owing to the high therapeutic efficacy and safety profile of this system compared to the free administration of the antibiotic. Full article

(This article belongs to the Topic Cystic Fibrosis)

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17 pages, 4241 KiB  

Open AccessArticle

CFTR Modulation Reduces SARS-CoV-2 Infection in Human Bronchial Epithelial Cells

by Virginia Lotti, Flavia Merigo, Anna Lagni, Andrea Di Clemente, Marco Ligozzi, Paolo Bernardi, Giada Rossini, Ercole Concia, Roberto Plebani, Mario Romano, Andrea Sbarbati, Claudio Sorio and Davide Gibellini

Cells 2022, 11(8), 1347; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11081347 - 15 Apr 2022

Cited by 14 | Viewed by 3479

Abstract

People with cystic fibrosis should be considered at increased risk of developing severe symptoms of COVID-19. Strikingly, a broad array of evidence shows reduced spread of SARS-CoV-2 in these subjects, suggesting a potential role for CFTR in the regulation of SARS-CoV-2 infection/replication. Here, [...] Read more.

People with cystic fibrosis should be considered at increased risk of developing severe symptoms of COVID-19. Strikingly, a broad array of evidence shows reduced spread of SARS-CoV-2 in these subjects, suggesting a potential role for CFTR in the regulation of SARS-CoV-2 infection/replication. Here, we analyzed SARS-CoV-2 replication in wild-type and CFTR-modified human bronchial epithelial cell lines and primary cells to investigate SARS-CoV-2 infection in people with cystic fibrosis. Both immortalized and primary human bronchial epithelial cells expressing wt or F508del-CFTR along with CRISPR/Cas9 CFTR-ablated clones were infected with SARS-CoV-2 and samples were harvested before and from 24 to 72 h post-infection. CFTR function was also inhibited in wt-CFTR cells with the CFTR-specific inhibitor IOWH-032 and partially restored in F508del-CFTR cells with a combination of CFTR modulators (VX-661+VX-445). Viral load was evaluated by real-time RT-PCR in both supernatant and cell extracts, and ACE-2 expression was analyzed by both western blotting and flow cytometry. SARS-CoV-2 replication was reduced in CFTR-modified bronchial cells compared with wild-type cell lines. No major difference in ACE-2 expression was detected before infection between wild-type and CFTR-modified cells, while a higher expression in wild-type compared to CFTR-modified cells was detectable at 72 h post-infection. Furthermore, inhibition of CFTR channel function elicited significant inhibition of viral replication in cells with wt-CFTR, and correction of CFTR function in F508del-CFTR cells increased the release of SARS-CoV-2 viral particles. Our study provides evidence that CFTR expression/function is involved in the regulation of SARS-CoV-2 replication, thus providing novel insights into the role of CFTR in SARS-CoV-2 infection and the development of therapeutic strategies for COVID-19. Full article

(This article belongs to the Topic Cystic Fibrosis)

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15 pages, 2282 KiB  

Open AccessArticle

The L467F-F508del Complex Allele Hampers Pharmacological Rescue of Mutant CFTR by Elexacaftor/Tezacaftor/Ivacaftor in Cystic Fibrosis Patients: The Value of the Ex Vivo Nasal Epithelial Model to Address Non-Responders to CFTR-Modulating Drugs

by Elvira Sondo, Federico Cresta, Cristina Pastorino, Valeria Tomati, Valeria Capurro, Emanuela Pesce, Mariateresa Lena, Michele Iacomino, Ave Maria Baffico, Domenico Coviello, Tiziano Bandiera, Federico Zara, Luis J. V. Galietta, Renata Bocciardi, Carlo Castellani and Nicoletta Pedemonte

Int. J. Mol. Sci. 2022, 23(6), 3175; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23063175 - 15 Mar 2022

Cited by 19 | Viewed by 3174

Abstract

Loss-of-function mutations of the CFTR gene cause cystic fibrosis (CF) through a variety of molecular mechanisms involving altered expression, trafficking, and/or activity of the CFTR chloride channel. The most frequent mutation among CF patients, F508del, causes multiple defects that can be, however, overcome [...] Read more.

Loss-of-function mutations of the CFTR gene cause cystic fibrosis (CF) through a variety of molecular mechanisms involving altered expression, trafficking, and/or activity of the CFTR chloride channel. The most frequent mutation among CF patients, F508del, causes multiple defects that can be, however, overcome by a combination of three pharmacological agents that improve CFTR channel trafficking and gating, namely, elexacaftor, tezacaftor, and ivacaftor. This study was prompted by the evidence of two CF patients, compound heterozygous for F508del and a minimal function variant, who failed to obtain any beneficial effects following treatment with the triple drug combination. Functional studies on nasal epithelia generated in vitro from these patients confirmed the lack of response to pharmacological treatment. Molecular characterization highlighted the presence of an additional amino acid substitution, L467F, in cis with the F508del variant, demonstrating that both patients were carriers of a complex allele. Functional and biochemical assays in heterologous expression systems demonstrated that the double mutant L467F-F508del has a severely reduced activity, with negligible rescue by CFTR modulators. While further studies are needed to investigate the actual prevalence of the L467F-F508del allele, our results suggest that this complex allele should be taken into consideration as plausible cause in CF patients not responding to CFTR modulators. Full article

(This article belongs to the Topic Cystic Fibrosis)

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18 pages, 2532 KiB  

Open AccessEditor’s ChoiceArticle

Evaluation of the Mucoadhesive Properties of Chitosan-Based Microstructured Lipid Carrier (CH-MLC)

by Marta Guerini, Giorgia Condrò and Paola Perugini

Pharmaceutics 2022, 14(1), 170; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14010170 - 12 Jan 2022

Cited by 11 | Viewed by 2786

Abstract

Different mucoadhesive systems have been studied in recent years to increase the residence time of the delivery systems and to prolong the release of the drug. The aim of this work was to evaluate the mucoadhesive properties of chitosan-based Microstructured Lipid Carrier (CH-MLC) [...] Read more.

Different mucoadhesive systems have been studied in recent years to increase the residence time of the delivery systems and to prolong the release of the drug. The aim of this work was to evaluate the mucoadhesive properties of chitosan-based Microstructured Lipid Carrier (CH-MLC) with a new approach which requires chitosan and mucin to be compacted into a tablet and mucoadhesion to be assessed on a non-mucoadhesive substrate. This type of test showed that chitosan maintains a close bond with mucin even in the presence of a fluid and even encapsulated in microparticles. After this, using a bioreactor, the release of N-acetylcysteine (NAC) from the microparticles (NA-CH-MLC) through a layer of mucus mimicking the pathological conditions of a patient with cystic fibrosis was tested. The release of the active from NAC-CH-MLC demonstrated how the chitosan inside the microparticles acts as a penetration enhancer and how the microparticles can impart a prolonged release over time. Full article

(This article belongs to the Topic Cystic Fibrosis)

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