title: Targeting a genetic defect: cystic fibrosis transmembrane conductance regulator modulators in cystic fibrosis.
abstract: Cystic fibrosis (CF) is caused by genetic mutations that affect the cystic fibrosis transmembrane conductance regulator (CFTR) protein. These mutations can impact the synthesis and transfer of the CFTR protein to the apical membrane of epithelial cells, as well as influencing the gating or conductance of chloride and bicarbonate ions through the channel. CFTR dysfunction results in ionic imbalance of epithelial secretions in several organ systems, such as the pancreas, gastrointestinal tract, liver and the respiratory system. Since discovery of the CFTR gene in 1989, research has focussed on targeting the underlying genetic defect to identify a disease-modifying treatment for CF. Investigated management strategies have included gene therapy and the development of small molecules that target CFTR mutations, known as CFTR modulators. CFTR modulators are typically identified by high-throughput screening assays, followed by preclinical validation using cell culture systems. Recently, one such modulator, the CFTR potentiator ivacaftor, was approved as an oral therapy for CF patients with the G551D-CFTR mutation. The clinical development of ivacaftor not only represents a breakthrough in CF care but also serves as a noteworthy example of personalised medicine.
authors: CFTR Biomarker Centre and Translational CF Research Group Christiane Herzog Cystic Fibrosis Centre, Paediatric Pulmonology and Immunology, Charité Universitätsmedizin Berlin, Berlin, Germany. Nico.Derichs@charite.de
authors: Nico
authors: N
authors: Derichs
mesh_terms: D000627:Aminophenols / Q000627:therapeutic use; D000818:Animals; D003550:Cystic Fibrosis / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000737:chemistry / Q000187:drug effects* / Q000235:genetics* / Q000378:metabolism; D055808:Drug Discovery / Q000379:methods; D020022:Genetic Predisposition to Disease; D015316:Genetic Therapy; D057166:High-Throughput Screening Assays; D006801:Humans; D058990:Molecular Targeted Therapy; D009154:Mutation; D010641:Phenotype; D057285:Precision Medicine; D011379:Prognosis; D011487:Protein Conformation; D015363:Quinolones / Q000627:therapeutic use; D019141:Respiratory System Agents / Q000627:therapeutic use*; D013329:Structure-Activity Relationship
chemical_list: D000627:Aminophenols; C505032:CFTR protein, human; D015363:Quinolones; D019141:Respiratory System Agents; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C545203:ivacaftor