title: Evidence of CFTR function in cystic fibrosis after systemic administration of 4-phenylbutyrate.
abstract: Most individuals with cystic fibrosis (CF) carry one or two mutations that result in a maturation defect of the full-length protein. One such mutation, deltaF508, results in a mutant membrane glycoprotein that fails to progress to the apical membrane, where the wild-type protein normally functions as a cyclic AMP-regulated chloride channel. 4-Phenylbutyrate (Buphenyl), an orally bioavailable short chain fatty acid, modulates heat shock protein expression and restores maturation of the deltaF508 protein in vitro and in vivo. We performed a randomized, double-blind, placebo-controlled, dose-escalation and safety study of Buphenyl in 19 adults with CF (homozygous deltaF508) to test the hypothesis that Buphenyl would be safe, well-tolerated, and associated with an increase in chloride transport in nasal epithelia. Three dose levels (20, 30, or 40 g divided t.i.d.) of drug or placebo were given for 1 week. Serial measurements of chloride transport by nasal potential difference (NPD) testing and metabolic safety testing were performed. A maximum tolerated dose of 20 g was defined based on minimal adverse reactions, the safety profile, and a statistically significant induction of chloride transport that was maximal by day 3. This short-term phase I/II study demonstrates proof of principle that modulation of deltaF508 CFTR biosynthesis and trafficking is a viable therapeutic approach for cystic fibrosis.
authors.affiliation: Departments of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA. pzeitli@jhmi.edu
authors.forename: Pamela L
authors.initials: PL
authors.lastname: Zeitlin
authors.forename: Marie
authors.initials: M
authors.lastname: Diener-West
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Rubenstein
authors.forename: Michael P
authors.initials: MP
authors.lastname: Boyle
authors.forename: Carlton K K
authors.initials: CK
authors.lastname: Lee
authors.forename: Lois
authors.initials: L
authors.lastname: Brass-Ernst
mesh_terms: D000328:Adult; D001693:Biological Transport, Active; D002712:Chlorides / Q000378:metabolism; D003550:Cystic Fibrosis / Q000188:drug therapy*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000187:drug effects*; D005260:Female; D006801:Humans; D008297:Male; D009297:Nasal Mucosa / Q000503:physiopathology; D010654:Phenylbutyrates / Q000009:adverse effects / Q000494:pharmacology*
chemical_list: C505032:CFTR protein, human; D002712:Chlorides; D010654:Phenylbutyrates; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C075773:4-phenylbutyric acid