title: Repairing the basic defect in cystic fibrosis - one approach is not enough.
abstract: Cystic fibrosis has attracted much attention in recent years due to significant advances in the pharmacological targeting of the basic defect underlying this recessive disorder: the deficient functional expression of mutant cystic fibrosis transmembrane conductance regulator (CFTR) chloride channels at the apical membrane of epithelial cells. However, increasing evidence points to the reduced efficacy of single treatments, thus reinforcing the need to combine several therapeutic strategies to effectively target the multiple basic defect(s). Protein-repair therapies that use potentiators (activating membrane-located CFTR) or correctors (promoting the relocation of intracellular-retained trafficking mutants of CFTR) in frequent mutations such as F508del and G551D have been put forward and made their way to the clinic with moderate to good efficiency. However, alternative (or additional) approaches targeting the membrane stability of mutant proteins, or correcting the cellular phenotype through a direct effect upon other ion channels (affecting the overall electrolyte transport or simply promoting alternative chloride transport) or targeting less frequent mutations (splicing variants, for example), have been proposed and tested in the field of cystic fibrosis (CF). Here, we cover the different strategies that rely on novel findings concerning the CFTR interactome and signalosome through which it might be possible to further influence the cellular trafficking and post-translational modification machinery (to increase rescued CFTR abundance and membrane stability). We also highlight the new data on strategies aiming at the regulation of sodium absorption or to increase chloride transport through alternative channels. The development and implementation of these complementary approaches will pave the way to combinatorial therapeutic strategies with increased benefit to CF patients.
authors.affiliation: BioISI - Biosystems & Integrative Sciences Institute, Faculty of Sciences, University of Lisboa, Portugal.
authors.forename: Carlos M
authors.initials: CM
authors.lastname: Farinha
authors.affiliation: BioISI - Biosystems & Integrative Sciences Institute, Faculty of Sciences, University of Lisboa, Portugal.|Department of Human Genetics, National Health Institute 'Dr. Ricardo Jorge', Lisboa, Portugal.
authors.forename: Paulo
authors.initials: P
authors.lastname: Matos
mesh_terms: D003550:Cystic Fibrosis / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics* / Q000378:metabolism; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D058990:Molecular Targeted Therapy / Q000379:methods*; D009154:Mutation; D017510:Protein Folding; D011499:Protein Processing, Post-Translational; D021381:Protein Transport
chemical_list: C505032:CFTR protein, human; D019005:Cystic Fibrosis Transmembrane Conductance Regulator
keywords: bypass approaches; correctors; cystic fibrosis; cystic fibrosis transmembrane conductance regulator; novel therapies; potentiators