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

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.

Keywords: correctors; drug repositioning; high-throughput screening; personalized medicine; potentiators; precision medicine.

Figure 1

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.

Figure 2

Predicted topology of CFTR protein. Notes: It is composed of two repeated units made of a MSD followed by a NBD. The two repeated units are linked by a R domain. The MSDs consist of six hydrophobic transmembrane helices (or TMD). Several transmembrane helices contain one or more charged amino acids that control anion permeability. Extracellular loop 4 (between TMD7 and TMD8) contains two N-glycosylation sites. Abbreviations: CFTR, cystic fibrosis transmembrane conductance regulator; MSD, membrane-spanning domain; NBD, nucleotide-binding domain; TMD: transmembrane domain; R, regulatory domain.

Figure 3

Overview of the most advance CFTR modulators in preclinical and clinical studies, with regard to the class of CFTR mutations and the primary defect of the corresponding mutant protein. Abbreviations: CFTR, cystic fibrosis transmembrane conductance regulator; PTC, premature termination codon; EGCG, epigallocatechin gallate; ER, endoplasmic reticulum; Ub, ubiquitin; mRNA, messenger RNA.