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

Nature Medicine volume 23, pages 590–600 (2017)Cite this article

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A Publisher Correction to this article was published on 22 June 2018

An Author Correction to this article was published on 22 June 2018

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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.

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Figure 1: Tα1 limits the inflammatory response in cystic fibrosis via IDO1.
Figure 2: Tα1 increases cell surface expression and stability of p.Phe508del-CFTR.
Figure 3: Tα1 rescues p.Phe508del-CFTR by promoting USP36 deubiquitination.
Figure 4: Tα1 rescues p.Phe508del-CFTR functional activity.
Figure 5: Tα1 rescues p.Phe508del-CFTR activity in CftrF508del mice.
Figure 6: Tα1 rescues p.Phe508del-CFTR activity in CF cells and human bronchial epithelial cells from subjects with CF.

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Change history

  • 22 June 2018

    In the version of this article originally published, some labels in Fig. 1f are incorrect. The "β-actin" labels on the second and fourth rows of blots should instead be "β-tubulin". The error has been corrected in the HTML and PDF versions of this article.

  • 22 June 2018

    In the version of this article originally published, the amino acid sequence for Tα1 described in the Online Methods is incorrect. The sequence is described as "Ac-SDAAVDTSSEITTJDLKEKKEVVEEAEN-OH". It should be "Ac-SDAAVDTSSEITTKDLKEKKEVVEEAEN-OH". The error has been corrected in the HTML and PDF versions of this article.

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Acknowledgements

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.

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Authors and Affiliations

  1. Department of Experimental Medicine, University of Perugia, Perugia, Italy

    Luigina Romani, Vasilis Oikonomou, Silvia Moretti, Rossana G Iannitti, Marilena Pariano, Luigi Sforna, Monica Borghi, Marina M Bellet, Francesca Fallarino, Maria Teresa Pallotta, Giuseppe Servillo, Paolo Puccetti & Mauro Pessia

  2. Department of Physiology and Biochemistry, Faculty of Medicine and Surgery, University of Malta, Msida, Malta

    Maria Cristina D'Adamo & Mauro Pessia

  3. Division of Genetics and Cell Biology, European Institute for Research in Cystic Fibrosis, San Raffaele Scientific Institute, Milan, Italy

    Valeria R Villella, Eleonora Ferrari & Luigi Maiuri

  4. Centre de Recherche des Cordeliers, INSERM U1138, Université Paris Descartes, Paris, France

    Guido Kroemer

  5. Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, Villejuif, France

    Guido Kroemer

  6. Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France

    Guido Kroemer

  7. Department of Women's and Children's Health, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden

    Guido Kroemer

  8. Department of Health Sciences, University of Piemonte Orientale, Novara, Italy

    Luigi Maiuri

  9. Department of Biochemistry and Molecular Medicine, George Washington University, School of Medicine and Health Sciences, Washington, DC, USA

    Allan L Goldstein

  10. University San Raffaele and IRCCS San Raffaele, Rome, Italy

    Enrico Garaci

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Contributions

V.O., R.G.I. and M. Pariano performed most immunoblotting and immunofluorescence experiments; R.G.I., M.B., S.M. and E.F. performed murine in vivo experiments; M.C.D'A., L.S. and M. Pessia performed electrophysiology experiments; F.F. and M.T.P. performed TLR9 colocalization experiments; M.M.B. and G.S. performed transfection experiments; V.R.V. performed Ussing chamber experiments; and A.L.G., L.M., G.K., M. Pessia, P.P., E.G. and L.R. designed the experiments, analyzed the data and wrote the paper.

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Correspondence to Luigina Romani.

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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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