title: Targeted therapies to improve CFTR function in cystic fibrosis.
abstract: Cystic fibrosis is the most common genetically determined, life-limiting disorder in populations of European ancestry. The genetic basis of cystic fibrosis is well established to be mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that codes for an apical membrane chloride channel principally expressed by epithelial cells. Conventional approaches to cystic fibrosis care involve a heavy daily burden of supportive treatments to combat lung infection, help clear airway secretions and maintain nutritional status. In 2012, a new era of precision medicine in cystic fibrosis therapeutics began with the licensing of a small molecule, ivacaftor, which successfully targets the underlying defect and improves CFTR function in a subgroup of patients in a genotype-specific manner. Here, we review the three main targeted approaches that have been adopted to improve CFTR function: potentiators, which recover the function of CFTR at the apical surface of epithelial cells that is disrupted in class III and IV genetic mutations; correctors, which improve intracellular processing of CFTR, increasing surface expression, in class II mutations; and production correctors or read-through agents, which promote transcription of CFTR in class I mutations. The further development of such approaches offers great promise for future therapeutic strategies in cystic fibrosis.
authors.affiliation: Institute of Cellular Medicine, Newcastle University and Department of Paediatric Respiratory Medicine, Great North Children's Hospital, Queen Victoria Road, Newcastle, NE1 4LP, UK. malcolm.brodlie@ncl.ac.uk.
authors.forename: Malcolm
authors.initials: M
authors.lastname: Brodlie
authors.affiliation: Department of Paediatric Respiratory Medicine, Great North Children's Hospital, Queen Victoria Road, Newcastle, NE1 4LP, UK.
authors.forename: Iram J
authors.initials: IJ
authors.lastname: Haq
authors.affiliation: Department of Paediatric Respiratory Medicine, Great North Children's Hospital, Queen Victoria Road, Newcastle, NE1 4LP, UK.
authors.forename: Katie
authors.initials: K
authors.lastname: Roberts
authors.affiliation: Centre for Infection and Immunity, Queen's University Belfast, Health Sciences Building, 97 Lisburn Road, Belfast, BT9 7BL, UK.
authors.forename: J Stuart
authors.initials: JS
authors.lastname: Elborn
mesh_terms: D000627:Aminophenols / Q000627:therapeutic use; D003550:Cystic Fibrosis / Q000188:drug therapy* / Q000235:genetics; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D058990:Molecular Targeted Therapy; D015363:Quinolones / Q000627:therapeutic use
chemical_list: D000627:Aminophenols; C505032:CFTR protein, human; D015363:Quinolones; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C545203:ivacaftor