Bioactive Thymosin Alpha-1 Does Not Influence F508del-CFTR Maturation and Activity

Andrea Armirotti, Valeria Tomati, Elizabeth Matthes, Guido Veit, Deborah M Cholon, Puay-Wah Phuan, Clarissa Braccia, Daniela Guidone, Martina Gentzsch, Gergely L Lukacs, Alan S Verkman, Luis J V Galietta, John W Hanrahan, Nicoletta Pedemonte

Research output: Contribution to journalArticlepeer-review


Deletion of phenylalanine 508 (F508del) in the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel is the most frequent mutation causing cystic fibrosis (CF). F508del-CFTR is misfolded and prematurely degraded. Recently thymosin a-1 (Tα-1) was proposed as a single molecule-based therapy for CF, improving both F508del-CFTR maturation and function by restoring defective autophagy. However, three independent laboratories failed to reproduce these results. Lack of reproducibility has been ascribed by the authors of the original paper to the use of DMSO and to improper handling. Here, we address these potential issues by demonstrating that Tα-1 changes induced by DMSO are fully reversible and that Tα-1 peptides prepared from different stock solutions have equivalent biological activity. Considering the negative results here reported, six independent laboratories failed to demonstrate F508del-CFTR correction by Tα-1. This study also calls into question the autophagy modulator cysteamine, since no rescue of mutant CFTR function was detected following treatment with cysteamine, while deleterious effects were observed when bronchial epithelia were exposed to cysteamine plus the antioxidant food supplement EGCG. Although these studies do not exclude the possibility of beneficial immunomodulatory effects of thymosin α-1, they do not support its utility as a corrector of F508del-CFTR.

Original languageEnglish
Pages (from-to)10310
JournalSci. Rep.
Issue number1
Publication statusPublished - Jul 16 2019


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