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.

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.

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 Progress in precision medicine in cystic fibrosis: a focus on CFTR modulator therapy

Breathe ◽  
2021 ◽  
Vol 17 (4) ◽  
pp. 210112
Author(s):  
Daniel H. Tewkesbury ◽  
Rebecca C. Robey ◽  
Peter J. Barry
Keyword(s):  
Cystic Fibrosis ◽  
Precision Medicine ◽  
Real World ◽  
Chloride Ion ◽  
Transmembrane Conductance Regulator ◽  
Therapeutic Approaches ◽  
Transmembrane Conductance ◽  
Cftr Protein ◽  
Cystic Fibrosis Transmembrane ◽  
Cftr Modulators

The genetic multisystem condition cystic fibrosis (CF) has seen a paradigm shift in therapeutic approaches within the past decade. Since the first clinical descriptions in the 1930s, treatment advances had focused on the downstream consequences of a dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR) chloride ion channel. The discovery of the gene that codes for CFTR and an understanding of the way in which different genetic mutations lead to disruption of normal CFTR function have led to the creation and subsequent licensing of drugs that target this process. This marks an important move towards precision medicine in CF and results from clinical trials and real-world clinical practice have been impressive. In this review we outline how CFTR modulator drugs restore function to the CFTR protein and the progress that is being made in this field. We also describe the real-world impact of CFTR modulators on both pulmonary and multisystem complications of CF and what this will mean for the future of CF care.

scholarly journals The combination of tezacaftor and ivacaftor in the treatment of patients with cystic fibrosis: clinical evidence and future prospects in cystic fibrosis therapy

2019 ◽  
Vol 13 ◽  
pp. 175346661984442 ◽  
Author(s):  
Sherstin T. Lommatzsch ◽  
Jennifer L. Taylor-Cousar
Keyword(s):  
Cystic Fibrosis ◽  
Clinical Evidence ◽  
Anion Channel ◽  
The United States ◽  
New Era ◽  
Sweat Chloride ◽  
Cftr Protein ◽  
Surface Liquid ◽  
Cftr Modulators ◽  
Epithelial Sodium Channel Enac

Years of tremendous study have dawned a new era for the treatment of cystic fibrosis (CF). For years CF care was rooted in the management of organ dysfunction resulting from the mal-effects of absent anion transport through the CF transmembrane regulator (CFTR) protein. CFTR, an adenosine triphosphate binding anion channel, has multiple functions, but primarily regulates the movement of chloride anions, thiocyanate and bicarbonate across luminal cell membranes. Additional roles include effects on other electrolyte channels such as the epithelial sodium channel (ENaC) and on pulmonary innate immunity. Inappropriate luminal anion movement leads to elevated sweat chloride concentrations, dehydrated airway surface liquid, overall viscous mucous production, and inspissated bile and pancreatic secretions. As a result, patients develop the well-known CF symptoms and disease-defining complications such as chronic cough, oily stools, recurrent pulmonary infections, bronchiectasis, chronic sinusitis and malnutrition. Traditionally, CF has been symptomatically managed, but over the past 6 years those with CF have been offered a new mode of therapy; CFTR protein modulation. These medications affect the basic defect in CF: abnormal CFTR function. Ivacaftor, approved for use in the United States in 2012, is the first medication in CF history to improve CFTR function at the molecular level. Its study and approval were followed by two additional CFTR modulators, lumacaftor/ivacaftor and tezacaftor/ivacaftor. To effectively use currently available CF therapies, clinicians should be familiar with the side effects of the drugs and their impacts on patient outcomes. As many new modulators are on the horizon, this information will equip providers to discuss the benefits and shortcomings of modulator therapy especially in the context of limited healthcare resources.

scholarly journals Elexacaftor/tezacaftor/ivacaftor in an individual with cystic fibrosis caused by a N1303K CFTR variant and infected with Mycobacterium abscessus

2021 ◽  
Author(s):  
E. Elson ◽  
Paula Capel ◽  
Jessica Haynes ◽  
Stephanie Duehlmeyer ◽  
Michelle Fischer ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Mycobacterium Abscessus ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Cftr Protein ◽  
Cystic Fibrosis Transmembrane ◽  
Protein Variants ◽  
Cftr Modulators ◽  
Clinical Stability

This report describes a case of a 15-year-old male with cystic fibrosis caused by N1303K and Q493X cystic fibrosis transmembrane conductance regulator (CFTR) protein variants. In this case, CFTR modulators including tezacaftor/ivacaftor and subsequently elexacaftor/tezacaftor/ivacaftor were utilized and resulted in clinical stability and improvement.

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.

Minitabletted pancreatin pangrol 10 000 iu and 25 000 iu efficacy and safety in patients with cystic fibrosis

2016 ◽  
Vol 7 (1) ◽  
pp. 22-26 ◽  
Author(s):  
Aleksandr V Orlov ◽  
Marina I Nikitina ◽  
Aleksandr A Pashkevich ◽  
Viktor N Kovalev
Keyword(s):  
Cystic Fibrosis ◽  
Adverse Events ◽  
Numerical Evaluation ◽  
Negative Symptoms ◽  
Pancreatic Insufficiency ◽  
Efficacy And Safety ◽  
Short Term ◽  
Enzyme Preparations ◽  
Drug Doses ◽  
Continue Therapy

The substitutive enzymatic therapy is vital in cystic fibrosis patients with pancreatic insufficiency. Usually patients are given enzymes at every meal. If it is necessary to replace one enzymatic remedy to another, the replacement should be done gradually (for 12-14 days). A comparative study of encapsulated enzyme preparations Creon 10 000 IU/25 000 IU and Pangrol 10 000 IU/25 000 IU safety, efficacy and tolerability was done in 20 patients with cystic fibrosis at the age of 11 months - 16 years. 13 people have got the doses in the calculation of the lipase up to 100 TU; and more than 100 TU - 7 people. Different drug doses effectiveness was determined according to faeces parameters and coprogram indicators. Numerical evaluation of the clinical efficacy and tolerability of both drugs was conducted through a questionnaire survey of patients and specialists. All patients completed the study. The effectiveness of the treatment according to coprogram was the same in both groups. In most cases, the process of transferring patients from Creon on Pangrol passed without the appearance of negative symptoms. It has been shown that encapsulated, mini-tablet pancreatin Pangrol well tolerated by patients. This allowed to 60 % of patients with cystic fibrosis change the treatment from Creon on Pangrol. Adverse events (10 %), detected in the process of transferring patients from one drug to another, were rare and short-term. The majority of physicians and patients prefer to continue therapy with Creon, according to their previous successful experience. Step-by-step scheme of replacing one enzymatic remedy on another is shown in this paper.

scholarly journals State of the Art on Approved Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Modulators and Triple-Combination Therapy

2021 ◽  
Vol 14 (9) ◽  
pp. 928
Author(s):  
Aniello Meoli ◽  
Valentina Fainardi ◽  
Michela Deolmi ◽  
Giulia Chiopris ◽  
Francesca Marinelli ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Young Children ◽  
Autosomal Recessive Disorder ◽  
Cftr Gene ◽  
Transmembrane Conductance Regulator ◽  
Inherited Disease ◽  
Transmembrane Conductance ◽  
Triple Combination Therapy ◽  
Cystic Fibrosis Transmembrane ◽  
Cftr Modulators

Cystic fibrosis (CF) is the most common life-limiting inherited disease in Caucasian populations, affecting approximately 80,000 people worldwide. CF is a complex multi-organ monogenic autosomal recessive disorder caused by a mutation in cystic fibrosis transmembrane conductance regulator (CFTR) gene. Since the discovery of the CFTR gene in 1989, more than 2000 mutations have been identified so far and about 240 can cause CF. Until recently, the treatment for CF was aimed to prevent and manage the manifestations of CFTR dysfunction, primarily recurrent pulmonary infections and pancreatic exocrine failure. Over the past few decades, the therapeutic approach to CF has been revolutionized by the development of a new class of small molecules called CFTR modulators that target specific defects caused by mutations in the CFTR gene. CFTR modulators have been shown to change profoundly the clinical course of the CF, leading to meaningful improvements in the lives of a large proportion of people of CF heterozygous for F508del, especially if started in young children. Further studies are needed to extend the use of triple CFTR modulation therapy also for young children in order to prevent the irreversible effects of the disease and for patients with very rare mutations with a personalized approach to treatment.

CFTR is functionally active in GnRH-expressing GT1–7 hypothalamic neurons

1999 ◽  
Vol 277 (3) ◽  
pp. C563-C571 ◽  
Author(s):  
Richard T. Weyler ◽  
Karin A. Yurko-Mauro ◽  
Ronald Rubenstein ◽  
Wouter J. W. Kollen ◽  
William Reenstra ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Neuronal Cell ◽  
Cftr Gene ◽  
Gene Transcript ◽  
Transmembrane Conductance Regulator ◽  
Hypothalamic Neurons ◽  
Cftr Protein ◽  
And Function ◽  
Human Brains ◽  
Gene Mrna

We have demonstrated the expression of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, mRNA, and protein within the rat and human brains, in areas regulating sexual differentiation and function. We have found that GT1–7, a gonadotropin-releasing hormone (GnRH)-secreting hypothalamic neuronal cell line, expresses the CFTR gene, mRNA, and protein and cAMP-dependent 36Cl efflux. A linear 7-pS Cl− conductance, which is stimulated by ATP and cAMP analogs and inhibited by glibenclamide, consistent with CFTR activity, has been identified in GT1–7 cells. Antisense oligo(dN) generated against exon 10 of the CFTR gene transcript (mRNA) inhibit GnRH secretion into media [312 ± 73, 850 ± 150, 963 ± 304, and 912 ± 74 pg GnRH/4 × 106 cells for antisense, sense, missense, and no oligo(dN), respectively; P < 0.029 for antisense oligo(dN)-treated vs. normal cells]. No changes in intracellular synthesis of GnRH were noted [1,400 ± 371 and 1,395 ± 384 pg GnRH/4 × 106 cells for antisense and sense oligo(dN), respectively]. Antisense oligo(dN), but not sense or missense oligo(dN), inhibited cAMP-dependent36Cl efflux. The expression of CFTR protein, detected by Western blotting, was also inhibited 68% by preincubation of cells with antisense oligo(dN). GT1–7 hypothalamic neurons express the CFTR gene, mRNA, and protein, which modulate neurosecretion. Abnormal neuropeptide vesicle trafficking by mutant CFTR may help to explain some of the diverse manifestations of cystic fibrosis.

scholarly journals Animal models of chronic lung infection with Pseudomonas aeruginosa: useful tools for cystic fibrosis studies

2008 ◽  
Vol 42 (4) ◽  
pp. 389-412 ◽  
Author(s):  
I Kukavica-Ibrulj ◽  
R C Levesque
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Animal Models ◽  
Pancreatic Insufficiency ◽  
Lung Infection ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Human Form ◽  
Cftr Protein ◽  
Chronic Lung Infection

Summary Cystic fibrosis (CF) is caused by a defect in the transmembrane conductance regulator (CFTR) protein that functions as a chloride channel. Dysfunction of the CFTR protein results in salty sweat, pancreatic insufficiency, intestinal obstruction, male infertility and severe pulmonary disease. In most patients with CF life expectancy is limited due to a progressive loss of functional lung tissue. Early in life a persistent neutrophylic inflammation can be demonstrated in the airways. The cause of this inflammation, the role of CFTR and the cause of lung morbidity by different CF-specific bacteria, mostly Pseudomonas aeruginosa, are not well understood. The lack of an appropriate animal model with multi-organ pathology having the characteristics of the human form of CF has hampered our understanding of the pathobiology and chronic lung infections of the disease for many years. This review summarizes the main characteristics of CF and focuses on several available animal models that have been frequently used in CF research. A better understanding of the chronic lung infection caused particularly by P. aeruginosa, the pathophysiology of lung inflammation and the pathogenesis of lung disease necessitates animal models to understand CF, and to develop and improve treatment.

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