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Cystic fibrosis transmembrane conductance regulator modulators in cystic fibrosis: current perspectives

View Article: PubMed Central - PubMed

ABSTRACT

Mutations of the CFTR gene cause cystic fibrosis (CF), the most common recessive monogenic disease worldwide. These mutations alter the synthesis, processing, function, or half-life of CFTR, the main chloride channel expressed in the apical membrane of epithelial cells in the airway, intestine, pancreas, and reproductive tract. Lung disease is the most critical manifestation of CF. It is characterized by airway obstruction, infection, and inflammation that lead to fatal tissue destruction. In spite of great advances in early and multidisciplinary medical care, and in our understanding of the pathophysiology, CF is still considerably reducing the life expectancy of patients. This review highlights the current development in pharmacological modulators of CFTR, which aim at rescuing the expression and/or function of mutated CFTR. While only Kalydeco® and Orkambi® are currently available to patients, many other families of CFTR modulators are undergoing preclinical and clinical investigations. Drug repositioning and personalized medicine are particularly detailed in this review as they represent the most promising strategies for restoring CFTR function in CF.

No MeSH data available.


Related in: MedlinePlus

Pathophysiology of CF lung disease and potential therapies targeting the basic defect or the symptoms.Note: In the absence of conclusive data on gene therapy, CFTR modulators are the most proximal therapy for CF currently in development.Abbreviations: CF, cystic fibrosis; CFTR, cystic fibrosis transmembrane conductance regulator; ENaC, epithelial sodium channel; mRNA, messenger RNA.
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f1-cpaa-8-127: Pathophysiology of CF lung disease and potential therapies targeting the basic defect or the symptoms.Note: In the absence of conclusive data on gene therapy, CFTR modulators are the most proximal therapy for CF currently in development.Abbreviations: CF, cystic fibrosis; CFTR, cystic fibrosis transmembrane conductance regulator; ENaC, epithelial sodium channel; mRNA, messenger RNA.

Mentions: CF is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, which was cloned and identified as the gene affected in CF in 1989.1CFTR gene encodes the main anion channel expressed in the epithelium. Additionally, CFTR is also expressed in many other cells types (eg, fibroblasts,2 neurons,3 cardiomyocytes,4 and immune cells5–7), where its function is not always well known. Among the 2,000+ CFTR mutations identified so far (http://genet.sickkids.on.ca), only a fraction of them causes CF. These CF-causing mutations induce a decrease or a loss of function of CFTR at the plasma membrane. In the lung, the lack of CFTR leads to dehydration of the airway surface liquid and drives the cascade of pathological events characteristic of CF (Figure 1).


Cystic fibrosis transmembrane conductance regulator modulators in cystic fibrosis: current perspectives
Pathophysiology of CF lung disease and potential therapies targeting the basic defect or the symptoms.Note: In the absence of conclusive data on gene therapy, CFTR modulators are the most proximal therapy for CF currently in development.Abbreviations: CF, cystic fibrosis; CFTR, cystic fibrosis transmembrane conductance regulator; ENaC, epithelial sodium channel; mRNA, messenger RNA.
© Copyright Policy
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC5036583&req=5

f1-cpaa-8-127: Pathophysiology of CF lung disease and potential therapies targeting the basic defect or the symptoms.Note: In the absence of conclusive data on gene therapy, CFTR modulators are the most proximal therapy for CF currently in development.Abbreviations: CF, cystic fibrosis; CFTR, cystic fibrosis transmembrane conductance regulator; ENaC, epithelial sodium channel; mRNA, messenger RNA.
Mentions: CF is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, which was cloned and identified as the gene affected in CF in 1989.1CFTR gene encodes the main anion channel expressed in the epithelium. Additionally, CFTR is also expressed in many other cells types (eg, fibroblasts,2 neurons,3 cardiomyocytes,4 and immune cells5–7), where its function is not always well known. Among the 2,000+ CFTR mutations identified so far (http://genet.sickkids.on.ca), only a fraction of them causes CF. These CF-causing mutations induce a decrease or a loss of function of CFTR at the plasma membrane. In the lung, the lack of CFTR leads to dehydration of the airway surface liquid and drives the cascade of pathological events characteristic of CF (Figure 1).

View Article: PubMed Central - PubMed

ABSTRACT

Mutations of the CFTR gene cause cystic fibrosis (CF), the most common recessive monogenic disease worldwide. These mutations alter the synthesis, processing, function, or half-life of CFTR, the main chloride channel expressed in the apical membrane of epithelial cells in the airway, intestine, pancreas, and reproductive tract. Lung disease is the most critical manifestation of CF. It is characterized by airway obstruction, infection, and inflammation that lead to fatal tissue destruction. In spite of great advances in early and multidisciplinary medical care, and in our understanding of the pathophysiology, CF is still considerably reducing the life expectancy of patients. This review highlights the current development in pharmacological modulators of CFTR, which aim at rescuing the expression and/or function of mutated CFTR. While only Kalydeco® and Orkambi® are currently available to patients, many other families of CFTR modulators are undergoing preclinical and clinical investigations. Drug repositioning and personalized medicine are particularly detailed in this review as they represent the most promising strategies for restoring CFTR function in CF.

No MeSH data available.


Related in: MedlinePlus