title: A novel treatment of cystic fibrosis acting on-target: cysteamine plus epigallocatechin gallate for the autophagy-dependent rescue of class II-mutated CFTR.
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.
authors.affiliation: Regional Cystic Fibrosis Center, Pediatric Unit, Department of Translational Medical Sciences, Federico II University, Naples 80131, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Tosco
authors.affiliation: Regional Cystic Fibrosis Center, Pediatric Unit, Department of Translational Medical Sciences, Federico II University, Naples 80131, Italy.
authors.forename: F
authors.initials: F
authors.lastname: De Gregorio
authors.affiliation: European Institute for Research in Cystic Fibrosis, Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan 20132, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Esposito
authors.affiliation: European Institute for Research in Cystic Fibrosis, Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan 20132, Italy.
authors.forename: D
authors.initials: D
authors.lastname: De Stefano
authors.affiliation: European Institute for Research in Cystic Fibrosis, Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan 20132, Italy.
authors.forename: I
authors.initials: I
authors.lastname: Sana
authors.affiliation: European Institute for Research in Cystic Fibrosis, Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan 20132, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Ferrari
authors.affiliation: Regional Cystic Fibrosis Center, Pediatric Unit, Department of Translational Medical Sciences, Federico II University, Naples 80131, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Sepe
authors.affiliation: Regional Cystic Fibrosis Center, Pediatric Unit, Department of Translational Medical Sciences, Federico II University, Naples 80131, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Salvadori
authors.affiliation: Regional Cystic Fibrosis Center, Pediatric Unit, Department of Translational Medical Sciences, Federico II University, Naples 80131, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Buonpensiero
authors.affiliation: Regional Cystic Fibrosis Center, Pediatric Unit, Department of Translational Medical Sciences, Federico II University, Naples 80131, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Di Pasqua
authors.affiliation: Otorhinolaryngology Unit, Monaldi Hospital, Naples 80131, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Grassia
authors.affiliation: Otorhinolaryngology Unit, Monaldi Hospital, Naples 80131, Italy.
authors.forename: C A
authors.initials: CA
authors.lastname: Leone
authors.affiliation: Department of Chemical, Materials and Production Engineering; Federico II University, Naples, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Guido
authors.affiliation: Department of Pharmacy, School of Pharmacy, Federico II University, Naples 80131, Italy.
authors.forename: G
authors.initials: G
authors.lastname: De Rosa
authors.affiliation: Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Naples 80138, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Lusa
authors.affiliation: SCDU of Pediatrics, Department of Health Sciences, University of Piemonte Orientale, Novara 28100, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Bona
authors.affiliation: Université Paris Descartes, Sorbonne Paris Cité, Paris, France.|Equipe 11 labellisée Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France.|Institut National de la Santé et de la Recherche Médicale, Paris, France.|Université Pierre et Marie Curie, Paris, France.
authors.forename: G
authors.initials: G
authors.lastname: Stoll
authors.affiliation: Equipe 11 labellisée Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France.
authors.forename: M C
authors.initials: MC
authors.lastname: Maiuri
authors.affiliation: Division of Cardiovascular and Diabetes Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK.
authors.forename: A
authors.initials: A
authors.lastname: Mehta
authors.affiliation: Equipe 11 labellisée Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France.|INSERM U1138, Centre de Recherche des Cordeliers, Paris, France.|Université Paris Descartes, Paris, France.|Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, Villejuif, France.|Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France.|Karolinska Institute, Department of Women's and Children's Health, Karolinska University Hospital, Stockholm 17176, Sweden.
authors.forename: G
authors.initials: G
authors.lastname: Kroemer
authors.affiliation: European Institute for Research in Cystic Fibrosis, Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan 20132, Italy.|SCDU of Pediatrics, Department of Health Sciences, University of Piemonte Orientale, Novara 28100, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Maiuri
authors.affiliation: Regional Cystic Fibrosis Center, Pediatric Unit, Department of Translational Medical Sciences, Federico II University, Naples 80131, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Raia
mesh_terms: D000293:Adolescent; D000818:Animals; D001343:Autophagy / Q000187:drug effects; D015415:Biomarkers / Q000032:analysis / Q000378:metabolism; D002392:Catechin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000633:toxicity; D002648:Child; D003543:Cysteamine / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D003550:Cystic Fibrosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D006720:Homozygote; D006801:Humans; D016209:Interleukin-8 / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D013183:Sputum / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000235:genetics / Q000378:metabolism
chemical_list: D015415:Biomarkers; D016209:Interleukin-8; D014409:Tumor Necrosis Factor-alpha; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D003543:Cysteamine; D002392:Catechin; C045651:epigallocatechin gallate