title: Thymosin α1 represents a potential potent single-molecule-based therapy for cystic fibrosis.
abstract: Cystic fibrosis (CF) is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) that compromise its chloride channel activity. The most common mutation, p.Phe508del, results in the production of a misfolded CFTR protein, which has residual channel activity but is prematurely degraded. Because of the inherent complexity of the pathogenetic mechanisms involved in CF, which include impaired chloride permeability and persistent lung inflammation, a multidrug approach is required for efficacious CF therapy. To date, no individual drug with pleiotropic beneficial effects is available for CF. Here we report on the ability of thymosin alpha 1 (Tα1)-a naturally occurring polypeptide with an excellent safety profile in the clinic when used as an adjuvant or an immunotherapeutic agent-to rectify the multiple tissue defects in mice with CF as well as in cells from subjects with the p.Phe508del mutation. Tα1 displayed two combined properties that favorably opposed CF symptomatology: it reduced inflammation and increased CFTR maturation, stability and activity. By virtue of this two-pronged action, Tα1 has strong potential to be an efficacious single-molecule-based therapeutic agent for CF.
authors.affiliation: Department of Experimental Medicine, University of Perugia, Perugia, Italy.
authors.forename: Luigina
authors.identifier: http://orcid.org/0000-0002-1356-525X
authors.initials: L
authors.lastname: Romani
authors.affiliation: Department of Experimental Medicine, University of Perugia, Perugia, Italy.
authors.forename: Vasilis
authors.initials: V
authors.lastname: Oikonomou
authors.affiliation: Department of Experimental Medicine, University of Perugia, Perugia, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Moretti
authors.affiliation: Department of Experimental Medicine, University of Perugia, Perugia, Italy.
authors.forename: Rossana G
authors.initials: RG
authors.lastname: Iannitti
authors.affiliation: Department of Physiology and Biochemistry, Faculty of Medicine and Surgery, University of Malta, Msida, Malta.
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: D'Adamo
authors.affiliation: European Institute for Research in Cystic Fibrosis, Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Valeria R
authors.initials: VR
authors.lastname: Villella
authors.affiliation: Department of Experimental Medicine, University of Perugia, Perugia, Italy.
authors.forename: Marilena
authors.initials: M
authors.lastname: Pariano
authors.affiliation: Department of Experimental Medicine, University of Perugia, Perugia, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Sforna
authors.affiliation: Department of Experimental Medicine, University of Perugia, Perugia, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Borghi
authors.affiliation: Department of Experimental Medicine, University of Perugia, Perugia, Italy.
authors.forename: Marina M
authors.identifier: http://orcid.org/0000-0001-7604-0189
authors.initials: MM
authors.lastname: Bellet
authors.affiliation: Department of Experimental Medicine, University of Perugia, Perugia, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Fallarino
authors.affiliation: Department of Experimental Medicine, University of Perugia, Perugia, Italy.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Pallotta
authors.affiliation: Department of Experimental Medicine, University of Perugia, Perugia, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Servillo
authors.affiliation: European Institute for Research in Cystic Fibrosis, Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Ferrari
authors.affiliation: Department of Experimental Medicine, University of Perugia, Perugia, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Puccetti
authors.affiliation: Centre de Recherche des Cordeliers, INSERM U1138, 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, Sweden.
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
authors.affiliation: Department of Experimental Medicine, University of Perugia, Perugia, Italy.|Department of Physiology and Biochemistry, Faculty of Medicine and Surgery, University of Malta, Msida, Malta.
authors.forename: Mauro
authors.initials: M
authors.lastname: Pessia
authors.affiliation: European Institute for Research in Cystic Fibrosis, Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy.|Department of Health Sciences, University of Piemonte Orientale, Novara, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Maiuri
authors.affiliation: Department of Biochemistry and Molecular Medicine, George Washington University, School of Medicine and Health Sciences, Washington, DC, USA.
authors.forename: Allan L
authors.initials: AL
authors.lastname: Goldstein
authors.affiliation: University San Raffaele and IRCCS San Raffaele, Rome, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Garaci
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D001343:Autophagy / Q000187:drug effects; D015153:Blotting, Western; D002460:Cell Line; D018118:Chloride Channels / Q000187:drug effects / Q000378:metabolism; D003550:Cystic Fibrosis / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000187:drug effects* / Q000276:immunology; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000187:drug effects / Q000276:immunology; D007249:Inflammation; D051379:Mice; D018181:Mice, Inbred CFTR; D018408:Patch-Clamp Techniques; D055550:Protein Stability / Q000187:drug effects; D000067996:RAW 264.7 Cells; D020545:Respiratory Mucosa / Q000166:cytology; D000077596:Thymalfasin; D013947:Thymosin / Q000031:analogs & derivatives* / Q000494:pharmacology; D043222:Ubiquitin Thiolesterase / Q000187:drug effects / Q000378:metabolism; D054875:Ubiquitination / Q000187:drug effects
chemical_list: D000276:Adjuvants, Immunologic; D018118:Chloride Channels; C116464:Clca3a1 protein, mouse; D016207:Cytokines; C583637:IDO1 protein, mouse; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D013947:Thymosin; D043222:Ubiquitin Thiolesterase; D000077596:Thymalfasin