Evidence of CFTR function in cystic fibrosis after systemic administration of 4-phenylbutyrate

Pamela L. Zeitlin, Marie Diener-West, Ronald C. Rubenstein, Michael P. Boyle, Carlton K.K. Lee, Lois Brass-Ernst

Research output: Contribution to journalArticlepeer-review

179 Scopus citations


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.

Original languageEnglish
Pages (from-to)119-126
Number of pages8
JournalMolecular Therapy
Issue number1
StatePublished - Jul 1 2002


  • Buphenyl
  • Butyrates
  • CFTR
  • Chloride
  • Clinical trial
  • Cystic fibrosis
  • Mutation
  • Sodium
  • Sweating
  • ΔF508


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