title: New horizons for cystic fibrosis treatment.
abstract: Cystic fibrosis is an inherited multi-system disease associated with chronic lung infection, malabsorption, salt loss syndromes, male infertility and leading to numerous comorbidities. The landscape in cystic fibrosis care has changed markedly with currently more adult patients than children in many countries. Over 2000 different mutations in the CFTR gene have been reported and the majority are extremely rare. Understanding how CFTR mutations translate to disturbed synthesis or function of the CFTR protein has opened the way to 'personalized' treatments to correct the basic defect. The first 2 drugs have reached the clinic: a CFTR potentiator to augment CFTR channel function, and the combination of this potentiator with a corrector to increase CFTR expression at the cell membrane. To obtain robust correction of CFTR expression at the cell membrane, combinations of correctors with additive efficacy are under investigation. Other mutation type-specific treatments under clinical investigation are premature stop codon-read through drugs and antisense oligonucleotides that correct the basic defect at the mRNA level. Restoring the defective gene by gene editing can already be achieved ex vivo. Mutation agnostic treatments are explored as well: stabilizing CFTR expression at the cell membrane, circumventing the CFTR channel by blocking or activating other ion channels, and gene therapy. Combinations of these therapies can be anticipated. The pipeline of corrective strategies under clinical investigation is increasing continuously and a rising number of pharmaceutical companies are entering the field.
authors.affiliation: Université Paris Descartes, Sorbonne Paris Cité, Paris, France; AP-HP, Hôpital Cochin, Service de Physiologie et Explorations Fonctionnelles, Paris, France. Electronic address: isabelle.fajac@parisdescartes.fr.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Fajac
authors.affiliation: University Hospital Gasthuisberg, Department of Pediatric Pulmonology, University of Leuven, Belgium. Electronic address: christiane.deboeck@uzleuven.be.
authors.forename: Kris
authors.initials: K
authors.lastname: De Boeck
mesh_terms: D002462:Cell Membrane / Q000378:metabolism; D003550:Cystic Fibrosis / Q000235:genetics / Q000503:physiopathology / Q000628:therapy*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D015195:Drug Design; D000072669:Gene Editing; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D009154:Mutation; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D019005:Cystic Fibrosis Transmembrane Conductance Regulator
keywords: CFTR; CFTR modulator; Corrector; Cystic fibrosis; Gene therapy; Potentiator; Read-through agent