scholarly journals Cystic fibrosis: current treatment and future direction

2021 ◽  
Vol 10 (4) ◽  
pp. 444
Author(s):  
Shreya Gupta ◽  
Niti Mittal ◽  
Mahesh C. Gupta
Keyword(s):  
Cystic Fibrosis ◽  
Chloride Channels ◽  
Genetic Disorder ◽  
Pancreatic Insufficiency ◽  
Genetic Defect ◽  
Disease Process ◽  
Holistic Approach ◽  
Current Treatment ◽  
Cftr Gene ◽  
Long Term Effects

Cystic fibrosis is an autosomal recessive genetic disorder, characterized by mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, leading to abnormality in the chloride channels of the mucus and sweat producing glands. Multiple organs systems are affected in this disorder, like respiratory system and gastrointestinal tract, severely impacting the patient’s quality of life, eventually leading on to several complications and death. Since the uncovering of the underlying genetic defect in cystic fibrosis (CF), our knowledge of the disease process has increased substantially, but we still lack a holistic approach to its management, which comprises of multiple facades, requiring both pharmacological and non-pharmacological or rehabilitatory approaches. So far, the therapeutic options were limited to targeting the consequences and complications of the disease, such as respiratory infection, mucus retention, pancreatic insufficiency, etc., but now several promising therapies may be able to address the underlying pathology rather than its long-term effects. This review summarizes the current and upcoming pharmacological options for CF, such as those targeting the CFTR gene defect directly, including gene editing, CFTR correctors and potentiators; drugs targeting the epithelial sodium channels (ENaC inhibitors); repositioning of some existing drugs and evaluating their role in CF; and understanding the disease better by transcriptomic approaches and the role of gut microbiota in the disease process and severity.

scholarly journals Sustained Glycemic Control With Ivacaftor in Cystic Fibrosis–Related Diabetes

2019 ◽  
Vol 7 ◽  
pp. 232470961984289 ◽  
Author(s):  
Francis Christian ◽  
Andrew Thierman ◽  
Erin Shirley ◽  
Karen Allen ◽  
Cory Cross ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Insulin Secretion ◽  
Glycemic Control ◽  
Pancreatic Insufficiency ◽  
Disease Process ◽  
Current Treatment ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Endogenous Insulin ◽  
Short Period

Cystic fibrosis–related diabetes (CFRD) is a common comorbidity in cystic fibrosis with pancreatic insufficiency occurring early in the disease process. Current treatment is exogenous insulin therapy as CFRD is due to impaired insulin secretion. Recent small studies have shown improvement in endogenous insulin secretion with a short period of ivacaftor therapy in primarily pediatric patients with cystic fibrosis transmembrane conductance regulator mutations amenable to potentiation. In this article, we present the case of an adult patient with long-standing CFRD who developed sustained improvement in glycemic control after initiation of ivacaftor.

Clinical and genetic characteristics of rare pathogenic variants of the CFTR gene in Russian patients with cystic fibrosis

2021 ◽  
Vol 31 (2) ◽  
pp. 148-158
Author(s):  
A. Yu. Voronkova ◽  
Yu. L. Melyanovskaya ◽  
N. V. Petrova ◽  
T. A. Adyan ◽  
E. K. Zhekaite ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Genetic Variants ◽  
Pancreatic Insufficiency ◽  
Protein Energy Malnutrition ◽  
Molecular Genetic ◽  
Clinical Manifestations ◽  
Cftr Gene ◽  
Genetic Characteristics ◽  
Missense Variants ◽  
Pathogenic Variants

The variety of clinical manifestations of cystic fibrosis is driven by the diversity of the CFTR gene nucleotide sequence. Descriptions of the clinical manifestations in patients with the newly identified genetic variants are of particular interest.The aim of this study was to describe clinical manifestations of the disease with the newly identified genetic variants.Methods. Data from Registry of patients with cystic fibrosis in the Russian Federation (2018) were used. The data review included three steps — the search for frequent mutations, Sanger sequencing, and the search for extensive rearrangements by MLPA. 38 pathogenic variants were identified that were not previously described in the international CFTR2 database. We selected and analyzed full case histories of 15 patients with 10 of those 38 pathogenic variants: p.Tyr84*, G1047S, 3321delG, c.583delC, CFTRdele13,14del18, CFTRdele19-22, c.2619+1G>A, c.743+2T>A, p.Glu1433Gly, and CFTRdel4-8del10-11.Results. A nonsense variant p.Tyr84* was found in 5 patients (0.08 %). Two missense variants c.3139G>A were found in 2 siblings (0.03 %). The c.4298A>G was found in 1 patient. Other variants were detected in a single patient (0.02 %) each. They included two variants of a deletion with a shift of the reading frame 3321delG and c.583delC, two splicing disorders c.2619+1G>A and c.743+2T>A, three extended rearrangements CFTRdele19-22, CFTRdele13,14del18, and CFTRdel4-8del10-11. The last two variants include 2 rearrangements on one allele, which cause the severe course in two young children. 8 of the 10 variants are accompanied by pancreatic insufficiency (PI). Among patients with p.Tyr84*, one had ABPA, one had liver transplantation, and all had Pseudomonas aeruginosa infection. Nasal polyps were diagnosed in 2 patients with p.Tyr84*, 1 with G1047S, 1 with CFTRdel4-8del10-11, and 1 patient with 3321delG, who also had osteoporosis and cystic fibrosis-related diabetes (CFRD). 2 patients with PI with 3321delG and CFTRdel4-8del10-11 genetic variants, and 1 with PI with p.Glu1433Gly genetic variant had severe protein-energy malnutrition (PEM).Conclusion. Clinical manifestations of previously undescribed CFTR genetic variants were described. 5/10 genetic variants should be attributed to class I, 3/10 – to class 7 of the function classification of pathogenic CFTR gene variants associated with transcription and translation disruptions. Class of the identified missense variants c.3139G>A and c.4298A>G has not been established and requires further functional, cultural, and molecular genetic studies.

scholarly journals Cystic Fibrosis in two Ghanaian Children

2021 ◽  
Vol 2 ◽  
pp. 167-170 ◽  
Author(s):  
Sandra Kwarteng Owusu ◽  
Gabrielle Obeng-Koranteng ◽  
Sandra Laryea Odai ◽  
Marie Charlyne Fatima Kilba ◽  
Parbie Abbeyquaye ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Genetic Testing ◽  
Severe Acute Malnutrition ◽  
Case Reports ◽  
African Descent ◽  
Genetic Disorder ◽  
Pancreatic Insufficiency ◽  
Acute Malnutrition ◽  
Diagnostic Tools ◽  
Sweat Testing

Cystic fibrosis (CF) is a severe life-limiting genetic disorder resulting from mutations in the cystic fibrosis transmembrane regulator gene and is reported to be more prevalent among Caucasians than people of African descent. The past three decades have seen a gradual increase in the reporting of CF in non-European populations with CF in all regions including Africa. We report on the first two known Ghanaian children diagnosed with CF presenting early in infancy. The first patient presented with severe acute malnutrition and persistent diarrhea resulting from severe exocrine pancreatic insufficiency. In the second patient, there were recurrent wheeze and recurrent pneumonia, severe dehydration with metabolic alkalosis. Diagnosis of CF in Ghana is challenging due to the absence of diagnostic tools such as sweat testing equipment. In the first patient, sweat testing and genetic testing were done in South Africa. In the second patient, sweat testing was not done but diagnosis was confirmed by genetic testing. Both patients presented with classical CF symptoms including Pseudomonas aeruginosa airway infection before age 6 months. Both children are currently alive and healthy on appropriate treatment. These case reports highlight the growing evidence of CF occurring in people of African descent and the diagnostic challenges faced in Africa.

scholarly journals Homozygous Deletion of the CFTR Gene Caused by Interstitial Maternal Isodisomy in a Peruvian Child with Cystic Fibrosis

2019 ◽  
Vol 08 (03) ◽  
pp. 147-152
Author(s):  
Flor Vásquez Sotomayor ◽  
Hugo Hernán Abarca-Barriga
Keyword(s):  
Cystic Fibrosis ◽  
Pancreatic Insufficiency ◽  
Chromosomal Rearrangements ◽  
Correct Diagnosis ◽  
Homozygous Deletion ◽  
Cftr Gene ◽  
Molecular Testing ◽  
Transmembrane Conductance Regulator ◽  
First Case ◽  
History Of

AbstractWe report the first case in Peru of cystic fibrosis caused by a homozygous deletion of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. A 10-month-old child who presented with meconium ileus and pancreatic insufficiency was tested for cystic fibrosis. Both parents of the child are of Peruvian background, are nonconsanguineous, and have no personal or family history of the disease. Chromosome microarray analysis revealed a homozygous deletion of the CFTR gene on chromosome 7 (7q31.2) within a maternally derived 12.8-Mb region of loss of heterozygosity with deletion of a region that includes the CFTR gene. Parental testing confirmed this finding. This case highlights the great importance of molecular testing and the study of chromosomal rearrangements in reaching a correct diagnosis and providing proper genetic counseling to the affected families.

scholarly journals Inflammatory Markers in Cystic Fibrosis Patients with LungPseudomonas AeruginosaInfection

1999 ◽  
Vol 8 (3) ◽  
pp. 159-167 ◽  
Author(s):  
A. L. Pukhalsky ◽  
N. I. Kapranov ◽  
E. A. Kalashnikova ◽  
G. V. Shmarina ◽  
L. A. Shabalova ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Antibiotic Treatment ◽  
Inflammatory Markers ◽  
Chloride Channels ◽  
Genetic Disorder ◽  
Peripheral Blood Lymphocytes ◽  
Tnf Α ◽  
Elevated Activity ◽  
The Relationship ◽  
Immunomodulating Drugs

Chronic endobronchial inflammation and bacterial infection are the main causes of morbidity and mortality in cystic fibrosis (CF), an autosomal recessive genetic disorder associated with improper function of chloride channels. Inflammation in CF lung is greatly amplified afterPseudomonas aeruginosainfection. In this study the relationship betweenP. aeruginosastatus and inflammatory markers has been investigated. Seventeen CF children in acute lung exacerbation were examined. CF patients withoutP. aeruginosainfection were characterized by elevated activity of sputum elastase, reduced response of peripheral blood lymphocytes to PHA and significant resistance to the antiproliferative action of glucocorticoids. These parameters were normalized after antibiotic treatment. The patients with prolongedP. aeruginosainfection demonstrated extremely high levels of elastase activity and elevated amounts of sputum IL-8 and TNF-α. Although antibiotic treatment resulted in clinical improvement, it failed to suppress excessive immune response in the lung. The data indicate that CF patients with prolongedP. aeruginosaneed the modified treatment, which should include immunomodulating drugs and protease inhibitors as well as antibacterial therapy.

Characterization of two distinct chloride channels in cultured dog pancreatic duct epithelial cells

1997 ◽  
Vol 272 (1) ◽  
pp. G172-G180 ◽  
Author(s):  
T. D. Nguyen ◽  
D. S. Koh ◽  
M. W. Moody ◽  
N. R. Fox ◽  
C. E. Savard ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Epithelial Cells ◽  
Pancreatic Duct ◽  
Chloride Channels ◽  
Pancreatic Insufficiency ◽  
Disulfonic Acid ◽  
Cl Channels ◽  
Vitro Model

Cl- secretion by pancreatic duct epithelial cells (PDEC) regulates cellular HCO3- secretion, an important component of the exocrine pancreas. In cystic fibrosis, for example, impaired function of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channel results in decreased pancreatic secretion and secondary pancreatic insufficiency. Studies of ion transport by PDEC have been hindered by the lack of a practical in vitro model. We have successfully cultured nontransformed dog PDEC on Vitrogen-coated permeable membranes overlying a feeder layer of myofibroblasts and report the characterization of Cl- channels in these cells. Cl- conductance, assessed through efflux of 125I from PDEC, was stimulated by agents acting via adenosine 3',5'-cyclic monophosphate (cAMP) or cytosolic Ca2+. The Cl- conductances activated by cAMP and Ca2+ were distinct, since they were differentially inhibited by 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid and, to a lesser extent, by 5-nitro-2-(3-phenylpropylamino)benzoic acid and diphenylamine-2 carboxylate. Patch-clamp studies confirmed the presence of Cl- channels activated by cAMP and Ca2+, with differential inhibition by 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid. The presence of CFTR Cl- channels in PDEC was confirmed by immunoblotting. These cultured PDEC are an optimal model for studies of pancreatic duct secretion.

scholarly journals Activated L-Arginine/Nitric Oxide Pathway in Pediatric Cystic Fibrosis and Its Association with Pancreatic Insufficiency, Liver Involvement and Nourishment: An Overview and New Results

2020 ◽  
Vol 9 (6) ◽  
pp. 2012
Author(s):  
Folke Brinkmann ◽  
Beatrice Hanusch ◽  
Manfred Ballmann ◽  
Sebene Mayorandan ◽  
Alexander Bollenbach ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Cystic Fibrosis ◽  
High Performance ◽  
Genetic Disorder ◽  
Pancreatic Insufficiency ◽  
Plasma Concentrations ◽  
Gas Chromatography Mass Spectrometry ◽  
No Production ◽  
Healthy Controls ◽  
Synthesis Inhibitor

Cystic fibrosis (CF; OMIM 219700) is a rare genetic disorder caused by a chloride channel defect, resulting in lung disease, pancreas insufficiency and liver impairment. Altered L-arginine (Arg)/nitric oxide (NO) metabolism has been observed in CF patients’ lungs and in connection with malnutrition. The aim of the present study was to investigate markers of the Arg/NO pathway in the plasma and urine of CF patients and to identify possible risk factors, especially associated with malnutrition. We measured the major NO metabolites nitrite and nitrate, Arg, a semi-essential amino acid and NO precursor, the NO synthesis inhibitor asymmetric dimethylarginine (ADMA) and its major urinary metabolite dimethylamine (DMA) in plasma and urine samples of 70 pediatric CF patients and 78 age-matched healthy controls. Biomarkers were determined by gas chromatography–mass spectrometry and high-performance liquid chromatography. We observed higher plasma Arg (90.3 vs. 75.6 µM, p < 0.0001), ADMA (0.62 vs. 0.57 µM, p = 0.03), Arg/ADMA ratio (148 vs. 135, p = 0.01), nitrite (2.07 vs. 1.95 µM, p = 0.03) and nitrate (43.3 vs. 33.1 µM, p < 0.001) concentrations, as well as higher urinary DMA (57.9 vs. 40.7 µM/mM creatinine, p < 0.001) and nitrate (159 vs. 115 µM/mM creatinine, p = 0.001) excretion rates in the CF patients compared to healthy controls. CF patients with pancreatic sufficiency showed plasma concentrations of the biomarkers comparable to those of healthy controls. Malnourished CF patients had lower Arg/ADMA ratios (p = 0.02), indicating a higher NO synthesis capacity in sufficiently nourished CF patients. We conclude that NO production, protein-arginine dimethylation, and ADMA metabolism is increased in pediatric CF patients. Pancreas and liver function influence Arg/NO metabolism. Good nutritional status is associated with higher NO synthesis capacity and lower protein-arginine dimethylation.

Cystic fibrosis affects chloride and sodium channels in human airway epithelia

1989 ◽  
Vol 67 (10) ◽  
pp. 1362-1365 ◽  
Author(s):  
Marek Duszyk ◽  
Andrew S. French ◽  
S. F. Paul Man
Keyword(s):  
Cystic Fibrosis ◽  
Sodium Channels ◽  
Chloride Channels ◽  
Genetic Defect ◽  
Airway Epithelial Cells ◽  
Cell Membrane Permeability ◽  
Single Type ◽  
Airway Epithelial ◽  
Patch Clamp Technique ◽  
The One

Abnormalities of epithelial function in cystic fibrosis (CF) have been linked to defects in cell membrane permeability to chloride or sodium ions. Recently, a class of chloride channels in airway epithelial cells have been reported to lack their usual sensitivity to phosphorylation via cAMP-dependent protein kinase, suggesting that CF could be due to a single genetic defect in these channels. We have examined single chloride and sodium channels in control and CF human nasal epithelia using the patch-clamp technique. The most common chloride channel was not the one previously associated with CF, but it was also abnormal in CF cells. In addition, the number of sodium channels was unusually high in CF. These findings suggest a wider disturbance of ion channel properties in CF than would be produced by a defect in a single type of channel.Key words: ion channels, cystic fibrosis, airway, epithelium.

CFTR knockdown stimulates lipid synthesis and transport in intestinal Caco-2/15 cells

2009 ◽  
Vol 297 (6) ◽  
pp. G1239-G1249 ◽  
Author(s):  
Geneviève Mailhot ◽  
Zaava Ravid ◽  
Soraya Barchi ◽  
Alain Moreau ◽  
Rémi Rabasa-Lhoret ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Pancreatic Insufficiency ◽  
Scavenger Receptor ◽  
Lipid Synthesis ◽  
Cftr Gene ◽  
Nutritional Deficiencies ◽  
Type I ◽  
Protein Activity ◽  
Fat Malabsorption ◽  
The Impact

Cystic fibrosis transmembrane conductance regulator (CFTR) is a chloride channel highly expressed in epithelial cells of the gastrointestinal tract. Mutations in the CFTR gene cause cystic fibrosis (CF), a disease characterized by pancreatic insufficiency, fat malabsorption, and steatorrhea. Despite the administration of pancreatic enzymes to normalize malabsorption, CF patients still experienced lipid fecal loss, nutritional deficiencies, and abnormalities in serum lipid profile, suggesting the presence of intrinsic defects in the intestinal handling of nutrients. The objective of the present study was to assess the impact of CFTR gene knockdown on intracellular lipid metabolism of the intestinal Caco-2/15 cell line. Partial CFTR gene inactivation led to cellular lipid accretion of phospholipids, triglycerides, and cholesteryl esters. Likewise, secretion of these lipid fractions was significantly increased following CFTR gene manipulation. As expected from these findings, the output of triglyceride-rich lipoproteins showed the same increasing pattern. Investigation of the mechanisms underlying these changes revealed that CFTR knockdown resulted in raised levels of apolipoproteins in cells and media and microsomal transfer protein activity, two important factors for the efficient assembly and secretion of lipoproteins. Similarly, scrutiny of the enzymatic monoacylglycerol acyltransferase and diacylglycerol acyltransferase, which exhibit dynamic function in triacylglycerol resynthesis and chylomicron formation in enterocytes, revealed a significant augmentation in their activity. Conversely, cholesterol uptake mediated by Niemann-Pick C1 like 1, Scavenger Receptor Class B Type I, and ATP-binding cassette G8 remains unaffected by genetic modification of CFTR. Collectively, these results highlight the role played by CFTR in intestinal handling of lipids and may suggest that factors other than defective CFTR are responsible for the abnormal intracellular events leading to fat malabsorption in CF patients.

Targeted therapy for cystic fibrosis

2021 ◽  
Vol 31 (2) ◽  
pp. 226-236
Author(s):  
S. I. Kutsev ◽  
V. L. Izhevskaya ◽  
E. I. Kondratyeva
Keyword(s):  
Cystic Fibrosis ◽  
Pancreatic Insufficiency ◽  
Mutant Gene ◽  
Bronchial Tree ◽  
Cftr Gene ◽  
Protein Activity ◽  
Enzyme Preparations ◽  
Calorie Diet ◽  
Cftr Protein ◽  
Cftr Modulators

The basic therapy of cystic fibrosis is currently aimed at slowing down the pathological processes associated with a decrease in the CFTR protein activity (cystic fibrosis transmembrane conductance regulator) in the gastrointestinal tract and the respiratory system. The pancreatic insufficiency is well compensated by replacement therapy with microsphere enzyme preparations and a high-calorie diet rich in proteins and fat. Chronic treatment of cystic fibrosis-related lung disease aims to improve the clearance of the bronchial tree, suppressing chronic bacterial infection and local chronic inflammation. However, no therapy was available to correct the defect in the gene or its product until 2012.The aim was to analyze literature on CFTR modulators, including their efficacy and safety, and assess the potential for developing new modulators to treat cystic fibrosis.Materials. The review included literature data (45 publications) on the use of CFTR modulators and international websites’ data.Results. Since the discovery of the CFTR gene in 1989, more than 2000 mutations or variants of the CFTR gene (hereinafter referred to as genetic variants) have been described. They interfere with the synthesis of the CFTR protein, its transport to the apical membrane of the cell, or disrupt its function as a channel for chloride anions. Although it is currently not possible to completely replace the mutant gene with a normal copy, small molecules have been identified that can modify the mutant CFTR protein and amend its function. The potential therapeutic measures are determined by class of the mutation. In clinical practice, pharmacological modeling of ion transport is currently possible only with the use of CFTR modulators: correctors and potentiators. The review defines these groups of drugs and describes 4 licensed CFTR modulators, including molecules of ivacaftor, lumacaftor, tezacaftor, elexacaftor. The data on the promising emerging next generation modulators and the prospects for the personalized selection of drugs using the assays on intestinal organoids are presented.

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