Pharmacologic restoration of delta F508 CFTR-mediated chloride current.
Cystic fibrosis (CF) is an autosomal inherited disorder caused by over 800 different mutations in the CFTR gene. The most common mutation, delta F508, causes a trafficking arrest in the endoplasmic reticulum and the CFTR protein is degraded. Restoration of CFTR trafficking in vitro restores cAMP-mediated chloride transport at the cell surface. The hypothesis of this discussion is that the short chain fatty acids, butyrate and 4-phenylbutyrate, up-regulate mature CFTR at the plasma membrane. Evidence that these compounds regulate CFTR production and maturation in part through effects on molecular chaperones in CF cells in culture is discussed. The oral drug, 4-phenylbutyrate, was tested in a Phase I clinical trial in CF subjects and further trials are underway. Other new therapeutic approaches directed at different classes of mutations in CFTR are also discussed. Chemical and pharmacologic agents that regulate endogenous gene expression at different steps in the biosynthetic processing pathway of a membrane glycoprotein will be needed to comprehensively treat a complex inherited disorder like cystic fibrosis.
Zeitlin
P L
PL
Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. pzeitli@jhmi.edu
D000818:Animals; D002087:Butyrates / Q000494:pharmacology; D018118:Chloride Channels / Q000378:metabolism / Q000502:physiology*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D004553:Electric Conductivity; D006801:Humans; D009154:Mutation / Q000502:physiology*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D013696:Temperature
D002087:Butyrates; C505032:CFTR protein, human; D018118:Chloride Channels; D019005:Cystic Fibrosis Transmembrane Conductance Regulator