Evidence of CFTR Function in Cystic Fibrosis after Systemic Administration of 4-Phenylbutyrate

• Published in: Molecular therapy Vol. 6; no. 1; pp. 119 - 126
• Main Authors: Zeitlin, Pamela L., Diener-West, Marie, Rubenstein, Ronald C., Boyle, Michael P., Lee, Carlton K.K., Brass-Ernst, Lois
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-07-2002; Elsevier Limited
• Subjects: Adult; Bioavailability; Biological Transport, Active; Buphenyl; butyrates; Catheters; CFTR; Chloride; Chlorides - metabolism; clinical trial; Cystic fibrosis; Cystic Fibrosis - drug therapy; Cystic Fibrosis Transmembrane Conductance Regulator - drug effects; Drug dosages; Fatty acids; Female; Gene therapy; Glycoproteins; Headaches; Heat shock proteins; Humans; Male; Metabolism; Mutation; Nasal Mucosa - physiopathology; Phenylbutyrates - adverse effects; Phenylbutyrates - pharmacology; sodium; sweating; ΔF508; United States > US; clinical trial; mutation; sodium; butyrates; cystic fibrosis; ΔF508; chloride; Buphenyl; sweating; CFTR
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1006/mthe.2002.0639

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, ΔF508, 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 ΔF508 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 ΔF508) 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 ΔF508 CFTR biosynthesis and trafficking is a viable therapeutic approach for cystic fibrosis.