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.
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We thank the primary cell culture service offered from the Italian Cystic Fibrosis Research Foundation for kindly providing us with the HBE cells. We thank B. Scholte (Erasmus Medical Center Rotterdam), who provided Cftrtm1EUR mice (F508del mice, European Economic Community European Coordination Action for Research in Cystic Fibrosis program EU FP6 SHMCT-2005-018932). We thank G. Teti (University of Messina, Italy) for providing us with the TLR9-GFP-transfected HEK293 cells. This study was supported by the Specific Targeted Research Project FunMeta (ERC-2011-AdG-293714 to L.R.). M.P. gratefully acknowledges a fellowship from the Italian Cystic Fibrosis Research Foundation.
A patent application by L.R. and E.G. is pending (filing date, 9 February 2016, RM2015A000056 and 102015000053089).
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Romani, L., Oikonomou, V., Moretti, S. et al. Thymosin α1 represents a potential potent single-molecule-based therapy for cystic fibrosis. Nat Med 23, 590–600 (2017). https://doi.org/10.1038/nm.4305
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