Format

Send to

Choose Destination
Cell Death Differ. 2016 Aug;23(8):1380-93. doi: 10.1038/cdd.2016.22. Epub 2016 Apr 1.

A novel treatment of cystic fibrosis acting on-target: cysteamine plus epigallocatechin gallate for the autophagy-dependent rescue of class II-mutated CFTR.

Author information

1
Regional Cystic Fibrosis Center, Pediatric Unit, Department of Translational Medical Sciences, Federico II University, Naples 80131, Italy.
2
European Institute for Research in Cystic Fibrosis, Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan 20132, Italy.
3
Otorhinolaryngology Unit, Monaldi Hospital, Naples 80131, Italy.
4
Department of Chemical, Materials and Production Engineering; Federico II University, Naples, Italy.
5
Department of Pharmacy, School of Pharmacy, Federico II University, Naples 80131, Italy.
6
Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Naples 80138, Italy.
7
SCDU of Pediatrics, Department of Health Sciences, University of Piemonte Orientale, Novara 28100, Italy.
8
Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
9
Equipe 11 labellisée Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France.
10
Institut National de la Santé et de la Recherche Médicale, Paris, France.
11
Université Pierre et Marie Curie, Paris, France.
12
Division of Cardiovascular and Diabetes Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK.
13
INSERM U1138, Centre de Recherche des Cordeliers, Paris, France.
14
Université Paris Descartes, Paris, France.
15
Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, Villejuif, France.
16
Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France.
17
Karolinska Institute, Department of Women's and Children's Health, Karolinska University Hospital, Stockholm 17176, Sweden.

Abstract

We previously reported that the combination of two safe proteostasis regulators, cysteamine and epigallocatechin gallate (EGCG), can be used to improve deficient expression of the cystic fibrosis transmembrane conductance regulator (CFTR) in patients homozygous for the CFTR Phe508del mutation. Here we provide the proof-of-concept that this combination treatment restored CFTR function and reduced lung inflammation (P<0.001) in Phe508del/Phe508del or Phe508del/null-Cftr (but not in Cftr-null mice), provided that such mice were autophagy-competent. Primary nasal cells from patients bearing different class II CFTR mutations, either in homozygous or compound heterozygous form, responded to the treatment in vitro. We assessed individual responses to cysteamine plus EGCG in a single-centre, open-label phase-2 trial. The combination treatment decreased sweat chloride from baseline, increased both CFTR protein and function in nasal cells, restored autophagy in such cells, decreased CXCL8 and TNF-α in the sputum, and tended to improve respiratory function. These positive effects were particularly strong in patients carrying Phe508del CFTR mutations in homozygosity or heterozygosity. However, a fraction of patients bearing other CFTR mutations failed to respond to therapy. Importantly, the same patients whose primary nasal brushed cells did not respond to cysteamine plus EGCG in vitro also exhibited deficient therapeutic responses in vivo. Altogether, these results suggest that the combination treatment of cysteamine plus EGCG acts 'on-target' because it can only rescue CFTR function when autophagy is functional (in mice) and improves CFTR function when a rescuable protein is expressed (in mice and men). These results should spur the further clinical development of the combination treatment.

PMID:
27035618
PMCID:
PMC4947669
DOI:
10.1038/cdd.2016.22
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center