Restoration of CFTR function in patients with cystic fibrosis carrying the F508del-CFTR mutation

Autophagy. 2014;10(11):2053-74. doi: 10.4161/15548627.2014.973737.


Restoration of BECN1/Beclin 1-dependent autophagy and depletion of SQSTM1/p62 by genetic manipulation or autophagy-stimulatory proteostasis regulators, such as cystamine, have positive effects on mouse models of human cystic fibrosis (CF). These measures rescue the functional expression of the most frequent pathogenic CFTR mutant, F508del, at the respiratory epithelial surface and reduce lung inflammation in Cftr(F508del) homozygous mice. Cysteamine, the reduced form of cystamine, is an FDA-approved drug. Here, we report that oral treatment with cysteamine greatly reduces the mortality rate and improves the phenotype of newborn mice bearing the F508del-CFTR mutation. Cysteamine was also able to increase the plasma membrane expression of the F508del-CFTR protein in nasal epithelial cells from F508del homozygous CF patients, and these effects persisted for 24 h after cysteamine withdrawal. Importantly, this cysteamine effect after washout was further sustained by the sequential administration of epigallocatechin gallate (EGCG), a green tea flavonoid, both in vivo, in mice, and in vitro, in primary epithelial cells from CF patients. In a pilot clinical trial involving 10 F508del-CFTR homozygous CF patients, the combination of cysteamine and EGCG restored BECN1, reduced SQSTM1 levels and improved CFTR function from nasal epithelial cells in vivo, correlating with a decrease of chloride concentrations in sweat, as well as with a reduction of the abundance of TNF/TNF-alpha (tumor necrosis factor) and CXCL8 (chemokine [C-X-C motif] ligand 8) transcripts in nasal brushing and TNF and CXCL8 protein levels in the sputum. Altogether, these results suggest that optimal schedules of cysteamine plus EGCG might be used for the treatment of CF caused by the F508del-CFTR mutation.

Keywords: BECN1/Beclin 1, autophagy-related; CF, cystic fibrosis; CFTR; CFTR, cystic fibrosis transmembrane conductance regulator; CHX, cycloheximide; CSNK2, casein kinase 2; CXCL2, chemokine (C-X-C motif) ligand 2; CXCL8, chemokine (C-X-C motif) ligand 8; EGCG, epigallocatechin gallate; FEV, forced expiratory volume; PM, plasma membrane; RPD, rectal potential difference; SQSTM1, sequestosome 1; TGM2, transglutaminase 2; TNF, tumor necrosis factor; autophagy; cysteamine; cystic fibrosis; epigallocatechin gallate; sweat chloride.

Publication types

  • Clinical Trial, Phase II
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Administration, Oral
  • Adolescent
  • Adult
  • Animals
  • Apoptosis Regulatory Proteins / metabolism
  • Beclin-1
  • Catechin / analogs & derivatives*
  • Catechin / pharmacology
  • Cell Membrane / metabolism
  • Child
  • Chlorides / chemistry
  • Cystamine / pharmacology*
  • Cysteamine / administration & dosage
  • Cystic Fibrosis / metabolism*
  • Cystic Fibrosis Transmembrane Conductance Regulator / genetics*
  • Female
  • Homozygote
  • Humans
  • Interleukin-8 / metabolism
  • Male
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Inbred CFTR
  • Mice, Transgenic
  • Mutation
  • Phenotype
  • Pilot Projects
  • Sequestosome-1 Protein
  • Tumor Necrosis Factor-alpha / metabolism
  • Young Adult


  • Adaptor Proteins, Signal Transducing
  • Apoptosis Regulatory Proteins
  • BECN1 protein, human
  • Beclin-1
  • Becn1 protein, mouse
  • CFTR protein, human
  • Chlorides
  • Interleukin-8
  • Membrane Proteins
  • SQSTM1 protein, human
  • Sequestosome-1 Protein
  • Tumor Necrosis Factor-alpha
  • cystic fibrosis transmembrane conductance regulator delta F508
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • Cysteamine
  • Catechin
  • epigallocatechin gallate
  • Cystamine