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F508del-CFTR is not corrected by thymosin α1

Nature Medicine volume 24, pages 890–891 (2018)Cite this article

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To the Editor: The most common disease-causing mutation in individuals with cystic fibrosis (CF) is p.Phe508del (also known as F508del) in cystic fibrosis transmembrane conductance regulator (CFTR), and over half of all patients with CF are homozygous for this mutation1. Recently, Romani et al.2 reported the observation that thymosin alpha 1 (Tα1), which is used in the clinic as an immunotherapeutic agent, can rescue CFTR function in human airway epithelial cells that express p.Phe508del-CFTR. The authors reported that both primary CF airway cells and a CFBE41o- cell line expressing p.Phe508del have increased p.Phe508del channel function and protein expression after treatment with Tα1. As Tα1 is approved for use in humans and has a known safety profile3, these results inspired us to write a commentary expressing enthusiasm for the potential application of this discovery for patients with CF4. We have subsequently sought to determine how robust the correction of p.Phe508del-CFTR by Tα1 is using our own assays and whether different sources of Tα1 produce similar levels of p.Phe508del-CFTR maturation and function in primary airway epithelial cells and the CFBE41o- cell line.

Primary human bronchial epithelial (HBE) cells from four patients expressing two copies of p.Phe508del were obtained from the Primary Airway Cell Biobank at the McGill CF Translational Research center (CFTRc) and cultured at the air–liquid interface, as described previously5,6. The cells were isolated from lung tissue obtained from the Institut de recherches clinique de Montréal (IRCM) with informed consent from patients after lung transplantation, following protocols approved by the Institutional Review Boards of the IRCM and McGill University. Primary HBE cells from two patients were initially studied 5 days after plating, as reported by the authors; however, under those conditions, the cells did not respond to the approved compound VX-809 (data not shown), a known p.Phe508del-CFTR corrector7, which was used here as a positive control. Primary HBE cells from four patients were then cultured for 4 weeks according to our standard protocol, which enables more complete differentiation. Tα1 from two different sources (CRIBI Biotechnology Center and Abcam) was studied. The former was redissolved in MilliQ H2O and relyophilized three times at CRIBI according to their standard procedures to eliminate any trifluoroacetic acid in the final product. Romani et al.2 used Tα1 from the same source. Peptide (3,066 Mr) from the latter source contained trace levels of acetic acid (final concentration, 16.7 nM); however, similar results were obtained after high-performance dialysis for 2 hours (molecular weight cutoff, 2 kDa; Slide-A-Lyzer, ThermoFisher). We tested Tα1 that had been dissolved initially in DMSO (final DMSO concentration, 0.1%) and also Tα1 dissolved in water. Sodium current was blocked by apical addition of amiloride (10 µM), and CFTR-dependent short-circuit current was measured by sequential, apical addition of the adenylyl cyclase activator forskolin (10 µM) and the CFTR potentiator genistein (50 µM). We also performed p.Phe508del-CFTR immunoblots prepared from cell lysates according to published methods8.

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Fig. 1: Effects of Tα1 on CFTR function in bronchial epithelial cells homozygous for the p.Phe508del mutation.

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Acknowledgements

We thank J. Goepp and the Primary Airway Cell Biobank (McGill University) for providing HBE cells, and we thank J. Hong and E. Sorscher (Emory University) for the CFBE41o- cell lines expressing p.Phe508del-CFTR. This work was supported by grants from CF Canada (2997) and the Canadian Institutes of Health Research (287879).

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Authors and Affiliations

  1. Department of Physiology, McGill University, Montréal, Québec, Canada

    Elizabeth Matthes & John W. Hanrahan

  2. Cystic Fibrosis Translational Research Centre, McGill University, Montréal, Québec, Canada

    Elizabeth Matthes, John W. Hanrahan & André M. Cantin

  3. Research Institute of McGill University Hospital Centre, Montréal, Québec, Canada

    John W. Hanrahan

  4. Service de Pneumologie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, Québec, Canada

    André M. Cantin

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Contributions

E.M. contributed to the design of the study, conducted the experiments and prepared the figure and figure legend. J.W.H. conceived and planned the experiments, analyzed the data and helped write the manuscript. A.M.C. helped write the manuscript with input from the other authors and supervised the project.

Corresponding author

Correspondence to André M. Cantin.

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Competing interests

A.M.C. has received honoraria as a speaker and consultant from Vertex Pharmaceuticals in 2016–2018. J.W.H. is cofounder and shareholder of Traffick Therapeutics, Inc. He consults for Engelhard Arzneimittel GmbH & Co., ERAD Therapeutics and Vertex Pharmaceuticals. Research funding is provided to his laboratory by Verona Pharma plc, Engelhard Arzneimittel GmbH & Co., and ERAD Therapeutics. J.W.H. has patent applications (awarded or pending) as co-inventor with Traffick Therapeutics (USPTO 62/306,287, Montreal, Canada), Verona Pharma (WO2015173551A1, Cardiff, UK) and Laurent Pharmaceuticals (USPTO 62/658,001, Montreal, Canada). J.W.H. is director of the CFTRc, which has a seminar series supported by Vertex. None of the investments, consulting activities or patents are related to Tα1.

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Matthes, E., Hanrahan, J.W. & Cantin, A.M. F508del-CFTR is not corrected by thymosin α1. Nat Med 24, 890–891 (2018). https://doi.org/10.1038/s41591-018-0079-6

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