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: Pamela L Zeitlin, Marie Diener-West, Ronald C Rubenstein, Michael P Boyle, Carlton K K Lee, Lois Brass-Ernst
• Journal: Molecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 6 Issue 1 Pg. 119-26 (Jul 2002) ISSN: 1525-0016 [Print] United States
• PMID: 12095312 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• CFTR protein, human
• Chlorides
• Phenylbutyrates
• Cystic Fibrosis Transmembrane Conductance Regulator
• 4-phenylbutyric acid

Topics

• Adult
• Biological Transport, Active
• Chlorides (metabolism)
• Cystic Fibrosis (drug therapy)
• Cystic Fibrosis Transmembrane Conductance Regulator (drug effects)
• Female
• Humans
• Male
• Nasal Mucosa (physiopathology)
• Phenylbutyrates (adverse effects, pharmacology)