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

Daniela De Stefano, Valeria R. Villella, Speranza Esposito, Antonella Tosco, Angela Sepe, Fabiola De Gregorio, Laura Salvadori, Rosa Grassia, Carlo A. Leone, Giuseppe De Rosa, Maria C. Maiuri, Massimo Pettoello-Mantovani, Stefano Guido, Anna Bossi, Anna Zolin, Andrea Venerando, Lorenzo A. Pinna, Anil Mehta, Gianni Bona, Guido Kroemer (Lead / Corresponding author)Luigi Maiuri, Valeria Raia

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    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 CftrF508del 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.

    Original languageEnglish
    Pages (from-to)2053-2074
    Number of pages22
    JournalAutophagy
    Volume10
    Issue number11
    Early online date27 Oct 2014
    DOIs
    Publication statusPublished - Nov 2014

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  • Cite this

    De Stefano, D., Villella, V. R., Esposito, S., Tosco, A., Sepe, A., De Gregorio, F., Salvadori, L., Grassia, R., Leone, C. A., De Rosa, G., Maiuri, M. C., Pettoello-Mantovani, M., Guido, S., Bossi, A., Zolin, A., Venerando, A., Pinna, L. A., Mehta, A., Bona, G., ... Raia, V. (2014). Restoration of CFTR function in patients with cystic fibrosis carrying the F508del-CFTR mutation. Autophagy, 10(11), 2053-2074. https://doi.org/10.4161/15548627.2014.973737