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Restoration of CFTR function in patients with cystic fibrosis carrying the F508del-CFTR mutation.
- Source :
-
Autophagy [Autophagy] 2014; Vol. 10 (11), pp. 2053-74. - Publication Year :
- 2014
-
Abstract
- 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.
- Subjects :
- Adaptor Proteins, Signal Transducing metabolism
Administration, Oral
Adolescent
Adult
Animals
Apoptosis Regulatory Proteins metabolism
Beclin-1
Catechin pharmacology
Cell Membrane metabolism
Child
Chlorides chemistry
Cysteamine administration & dosage
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
Catechin analogs & derivatives
Cystamine pharmacology
Cystic Fibrosis metabolism
Cystic Fibrosis Transmembrane Conductance Regulator genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1554-8635
- Volume :
- 10
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Autophagy
- Publication Type :
- Academic Journal
- Accession number :
- 25350163
- Full Text :
- https://doi.org/10.4161/15548627.2014.973737