Thymosin α1 represents a potential potent single-molecule-based therapy for cystic fibrosis

• Published in: Nature Medicine Vol. 23; no. 5; pp. 590 - 600
• Main Authors: Romani, Luigina, Oikonomou, Vasilis, Moretti, Silvia, Iannitti, Rossana G, D'Adamo, Maria Cristina, Villella, Valeria R, Pariano, Marilena, Sforna, Luigi, Borghi, Monica, Bellet, Marina M, Fallarino, Francesca, Pallotta, Maria Teresa, Servillo, Giuseppe, Ferrari, Eleonora, Puccetti, Paolo, Kroemer, Guido, Pessia, Mauro, Maiuri, Luigi, Goldstein, Allan L, Garaci, Enrico
• Format: Journal Article Magazine Article
• Language: English
• Published: New York Nature Publishing Group US 01.05.2017; Nature Publishing Group
• Subjects: 13/1; 13/109; 13/21; 13/89; 14/63; 38/61; 64/60; 692/308; 692/308/1426; 82/80; 9/74; Adjuvants, Immunologic - pharmacology; Animals; Autophagy - drug effects; Biomedicine; Blotting, Western; Cancer Research; Cell Line; Chloride Channels - drug effects; Chloride Channels - metabolism; Cystic Fibrosis - genetics; Cystic Fibrosis - immunology; Cystic Fibrosis - metabolism; Cystic Fibrosis Transmembrane Conductance Regulator - drug effects; Cystic Fibrosis Transmembrane Conductance Regulator - genetics; Cystic Fibrosis Transmembrane Conductance Regulator - metabolism; Cytokines - drug effects; Cytokines - immunology; Disease Models, Animal; Epithelial Cells - drug effects; Epithelial Cells - metabolism; Fluorescent Antibody Technique; Humans; Immunohistochemistry; Immunoprecipitation; Indoleamine-Pyrrole 2,3,-Dioxygenase - drug effects; Indoleamine-Pyrrole 2,3,-Dioxygenase - immunology; Infectious Diseases; Inflammation; Life Sciences; Metabolic Diseases; Mice; Mice, Inbred CFTR; Molecular Medicine; Neurosciences; Patch-Clamp Techniques; Protein Stability - drug effects; RAW 264.7 Cells; Respiratory Mucosa - cytology; Thymalfasin; Thymosin - analogs & derivatives; Thymosin - pharmacology; Ubiquitin Thiolesterase - drug effects; Ubiquitin Thiolesterase - metabolism; Ubiquitination - drug effects
• ISSN: 1078-8956; 1546-170X; 1546-170X; 1744-7933
• DOI: 10.1038/nm.4305

Thymosin α1 is used in the clinic as a treatment in viral disease and acts as an anti-inflammatory. Here it was found to also correct the misfolding of mutant CTFR and potentiate its activity, thus improving outcome in a mouse model of cystic fibrosis. 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.