scholarly journals Unravelling the Regions of Mutant F508del-CFTR More Susceptible to the Action of Four Cystic Fibrosis Correctors

2019 ◽  
Vol 20 (21) ◽  
pp. 5463 ◽  
Author(s):  
Amico ◽  
Brandas ◽  
Moran ◽  
Baroni
Keyword(s):  
Cystic Fibrosis ◽  
Bacterial Infections ◽  
Chloride Concentration ◽  
Hek293 Cells ◽  
Transmembrane Conductance Regulator ◽  
Quinazoline Derivative ◽  
Sweat Chloride ◽  
Cftr Protein ◽  
Trafficking Defects ◽  
The Stability

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.

scholarly journals Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Ubiquitylation as a Novel Pharmaceutical Target for Cystic Fibrosis

2020 ◽  
Vol 13 (4) ◽  
pp. 75 ◽  
Author(s):  
Ryosuke Fukuda ◽  
Tsukasa Okiyoneda
Keyword(s):  
Cystic Fibrosis ◽  
Structural Stability ◽  
Interacting Proteins ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Surrounding Environment ◽  
Cftr Protein ◽  
The Stability ◽  
And Function ◽  
Cystic Fibrosis Transmembrane

Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene decrease the structural stability and function of the CFTR protein, resulting in cystic fibrosis. Recently, the effect of CFTR-targeting combination therapy has dramatically increased, and it is expected that add-on drugs that modulate the CFTR surrounding environment will further enhance their effectiveness. Various interacting proteins have been implicated in the structural stability of CFTR and, among them, molecules involved in CFTR ubiquitylation are promising therapeutic targets as regulators of CFTR degradation. This review focuses on the ubiquitylation mechanism that contributes to the stability of mutant CFTR at the endoplasmic reticulum (ER) and post-ER compartments and discusses the possibility as a pharmacological target for cystic fibrosis (CF).

scholarly journals The Application of Bicarbonate Recovers the Chemical-Physical Properties of Airway Surface Liquid in Cystic Fibrosis Epithelia Models

Biology ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 278
Author(s):  
Loretta Ferrera ◽  
Valeria Capurro ◽  
Livia Delpiano ◽  
Ambra Gianotti ◽  
Oscar Moran
Keyword(s):  
Cystic Fibrosis ◽  
Bacterial Infections ◽  
Fluid Transport ◽  
Airway Surface Liquid ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Osmotic Solution ◽  
Cftr Protein ◽  
Surface Liquid ◽  
Cystic Fibrosis Transmembrane

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. Deletion of phenylalanine at position 508, p.F508del, the most frequent mutation among CF patients, causes a folding and traffic defect, resulting in a dramatic reduction in the CFTR expression. To investigate whether the direct application of bicarbonate could modify the properties of the airway surface liquid (ASL), we measured the micro-viscosity, fluid transport and pH of human bronchial epithelial cells monolayers. We have demonstrated that the treatment of a CF-epithelia with an iso-osmotic solution containing bicarbonate is capable of reducing both, the ASL viscosity and the apical fluid re-absorption. We suggest the possibility of design a supportive treatment based on topical application of bicarbonate, or any other alkaline buffer.

scholarly journals Real Life Evaluation of the Multi-organ Effects of Lumacaftor/Ivacaftor on F508del Homozygous Cystic Fibrosis Patients

2021 ◽  
Author(s):  
Karin Yaacoby-Bianu ◽  
Zeev Schnapp ◽  
Ilana Koren ◽  
Anat Ilivitzki ◽  
Mohamed Khatib ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Mineral Metabolism ◽  
Real Life ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Sweat Chloride ◽  
Registration Number ◽  
Cftr Protein ◽  
One Year ◽  
And Function

Abstract Background: Lumacaftor/Ivacaftor (LUM-IVA), a cystic fibrosis transmembrane conductance regulator (CFTR) protein corrector-potentiator combination, improves lung function and reduces pulmonary exacerbations (PEx) in F508del homozygous CF patients. However, the systemic effects of LUM-IVA outside the respiratory and nutritional domains have not yet been thoroughly investigated.Methods: A prospective, real-world, one-year study was performed on F508del homozygous adult CF patients who commenced treatment with LUM-IVA. Pancreatic function, bone metabolism, fertility status, nutritional and pulmonary factors were evaluated. Results: 12 patients with a mean age of 28.3 years (18.6-43.9) were recruited. Following 12 months of treatment, no changes were detected in glucose, insulin, c-peptide or BMI values. A significant relative decrease in mean alkaline-phosphatase levels (122.8 U/L vs 108, p=0.008) and a trend toward an increase in calcium levels (9.5 vs 9.8 mg/dL, p=0.0681) were observed. A non-significant improvement in mean DEXA spine t-score after a year of treatment (-2.1 vs -1.6, n=4, p=0.12) was detected. Sweat chloride concentrations decreased significantly after treatment (-21.4 mEq/L; p=0.003). Pulmonary outcome evaluations revealed improvement in spirometry values during the first three months (FEV1 by 5.7% p=0.019, FEF25-75 by 4.3% p=0.035) with no change in chest CT Bhalla score and CFQR after one year. There was also a shift from IV to oral antibiotics for PEx treatment.Conclusions: After a year of treatment, a stabilization was observed in the pancreatic indices, nutritional status, structure and function of the lungs, with a beneficial effect on bone mineral metabolism and CFTR function. Additional studies should investigate the effect of CFTR modulators on extra-pulmonary manifestations.The ClinicalTrials.gov registration number of the study is NCT04623879, registered on 10/11/2020, “retrospectively registered”.

Outcomes of Cystic Fibrosis Screening–Positive Infants With Inconclusive Diagnosis at School Age

PEDIATRICS ◽  
2021 ◽  
Author(s):  
Tanja Gonska ◽  
Katherine Keenan ◽  
Jacky Au ◽  
Annie Dupuis ◽  
Mark A. Chilvers ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Chloride Concentration ◽  
Predictive Biomarkers ◽  
School Age ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Sweat Chloride ◽  
Sweat Testing ◽  
Prospective Longitudinal ◽  
Cystic Fibrosis Transmembrane

BACKGROUND AND OBJECTIVES Cystic fibrosis (CF) screen–positive infants with an inconclusive diagnosis (CFSPID) are infants in whom sweat testing and genetic analysis does not resolve a CF diagnosis. Lack of knowledge about the health outcome of these children who require clinical follow-up challenges effective consultation. Early predictive biomarkers to delineate the CF risk would allow a more targeted approach to these children. METHODS Prospective, longitudinal, multicenter, Canada-wide cohort study of CF positive–screened newborns with 1 to 2 cystic fibrosis transmembrane conductance regulator gene variants, of which at least 1 is not known to be CF-causing and/or a sweat chloride between 30 and 59 mmol/L. These were monitored for conversion to a CF diagnosis, pulmonary, and nutritional outcomes. RESULTS The mean observation period was 7.7 (95% confidence interval 7.1 to 8.4) years. A CF diagnosis was established for 24 of the 115 children with CFSPID (21%) either because of reinterpretation of the cystic fibrosis transmembrane conductance regulator genotype or because of increase in sweat chloride concentration ≥60 mmol/L. An initial sweat chloride of ≥40 mmol/l predicted conversion to CF on the basis of sweat testing. The 91 remaining children with CFSPID were pancreatic sufficient and showed normal growth until school age. Pulmonary function as well as lung clearance index in a subgroup of children with CFSPID were similar to that of healthy controls. CONCLUSIONS Children with CFSPID have good nutritional and pulmonary outcomes at school age, but rates of reclassifying the diagnosis are high. The initial sweat chloride test can be used as a biomarker to predict the risk for CF in CFSPID.

PRO–CF–MED, Clinical Proof of concept for a RNA–targeting Oligonucleotide for a Cystic fibrosis–F508del MEDication, Horizon2020

Impact ◽  
2018 ◽  
Vol 2018 (3) ◽  
pp. 52-54
Author(s):  
Nicolas Lamontagne
Keyword(s):  
Cystic Fibrosis ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Rna Targeting ◽  
Threatening Condition ◽  
Life Threatening ◽  
Cftr Protein ◽  
Disease Modifying ◽  
Cystic Fibrosis Transmembrane ◽  
Specific Challenge

Cystic fibrosis (CF) is a progressive life–shortening disease caused by a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene leading to a dysfunctional CFTR protein. The disease affects over 70,000 patients worldwide and while many mutations are known, the F508del mutation affects 90% of all patients. The absence of CFTR in the plasma membrane leads to a dramatic decrease in chloride efflux, resulting in viscous mucus that causes severe symptoms in vital organs like the lungs and intestines. For CF patients that suffer from the life threatening F508del mutation only palliative treatment exist. PRO–CF–MED addresses the specific challenge of this call by introducing the first disease modifying medication for the treatment of the CF patients with F508del mutation. The PRO–CF–MED project has been designed to assess the potential clinical efficacy of QR–010, an innovative disease modifying oligonucleotide–based treatment for F508del patients. Partners within PRO–CF–MED have generated very promising preclinical evidence for QR–010 which allows for further clinical assessment of QR–010 in clinical trials. PRO–CF–MED will enable the fast translation of QR–010 towards clinical practice and market authorisation. PRO–CF–MED has the potential to transform this life–threatening condition into a manageable one.

scholarly journals Cystic Fibrosis: Improving quality of life

2021 ◽  
Vol 8 (2) ◽  
pp. 91-96
Author(s):  
Sunil Chaudhry
Keyword(s):  
Quality Of Life ◽  
Cystic Fibrosis ◽  
Sweat Glands ◽  
Common Mutation ◽  
Close Monitoring ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Estimate Frequency ◽  
Cftr Protein

Cystic Fibrosis (CF) or Mucoviscidosis is an inherited condition. In cystic fibrosis transmembrane conductance regulator (CFTR) protein does not functions properly i.e regulation of fluids and salts outside the cells. Cystic fibrosis affects exocrine glands eg., the mucus-secreting and sweat glands in the respiratory and digestive systems. The frequency of common mutation F508del (deletion of phenylalanine residue at position 508) in children is between 19% and 34%. The estimate frequency of CF as 1:10,000 to 1:40,000 in children. There is no cure for cystic fibrosis, but treatment can reduce symptoms and complications to improve quality of life. Close monitoring and early, aggressive intervention is recommended to slow the progression of CF, which can lead to possible longer life.

scholarly journals Targeted replacement of full-length CFTR in human airway stem cells by CRISPR/Cas9 for pan-mutation correction in the endogenous locus

2021 ◽  
Author(s):  
Sriram Vaidyanathan ◽  
Ron Baik ◽  
Lu Chen ◽  
Dawn T. Bravo ◽  
Carlos J. Suarez ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Stem Cells ◽  
Upper Airway ◽  
Pathogenic Mutation ◽  
Monogenic Disease ◽  
Transmembrane Conductance Regulator ◽  
Epithelial Monolayers ◽  
Cftr Protein ◽  
Almost All ◽  
Air Liquid Interface

AbstractCystic fibrosis (CF) is a monogenic disease caused by impaired production and/or function of the cystic fibrosis transmembrane conductance regulator (CFTR) protein. Although we have previously shown correction of the most common pathogenic mutation, there are many other pathogenic mutations throughout the CF gene. An autologous airway stem cell therapy in which the CFTR cDNA is precisely inserted into the CFTR locus may enable the development of a durable cure for almost all CF patients, irrespective of the causal mutation. Here, we use CRISPR/Cas9 and two adeno-associated viruses (AAV) carrying the two halves of the CFTR cDNA to sequentially insert the full CFTR cDNA along with a truncated CD19 (tCD19) enrichment tag in upper airway basal stem cells (UABCs) and human bronchial basal stem cells (HBECs). The modified cells were enriched to obtain 60-80% tCD19+ UABCs and HBECs from 11 different CF donors with a variety of mutations. Differentiated epithelial monolayers cultured at air-liquid interface showed restored CFTR function that was >70% of the CFTR function in non-CF controls. Thus, our study enables the development of a therapy for almost all CF patients, including patients who cannot be treated using recently approved modulator therapies.

scholarly journals Elexacaftor-Tezacaftor-Ivacaftor: The First Triple-Combination Cystic Fibrosis Transmembrane Conductance Regulator Modulating Therapy

2020 ◽  
Vol 25 (3) ◽  
pp. 192-197 ◽  
Author(s):  
Kaden Ridley ◽  
Michelle Condren
Keyword(s):  
Cystic Fibrosis ◽  
Clinical Trials ◽  
Genetic Mutations ◽  
Transmembrane Conductance Regulator ◽  
Triple Combination ◽  
Transmembrane Conductance ◽  
Sweat Chloride ◽  
Cystic Fibrosis Transmembrane

Elexacaftor-tezacaftor-ivacaftor is a newly approved triple-combination cystic fibrosis transmembrane conductance regulator (CFTR) modulating therapy that contains 2 correctors and a potentiator of the CFTR channel. Its labeled indication for use is for persons 12 years of age and older with at least 1 F508del mutation for the CFTR gene. This drug combination provides potential therapy to many patients who had previously been excluded from CFTR modulation therapy due to the nature of their genetic mutations. The efficacy demonstrated in clinical trials surpasses the currently available therapies related to lung function, quality of life, sweat chloride reduction, and reducing exacerbations. The most common adverse events seen in clinical trials included rash and headache, and laboratory monitoring is recommended to evaluate liver function. Continued evaluation of patient data is needed to confirm its long-term safety and efficacy. Elexacaftor-tezacaftor-ivacaftor is a monumental and encouraging therapy for cystic fibrosis; however, approximately 10% of the CF population are not candidates for this or any other CFTR modulation therapy.

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