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Editorial
Failure of TRPC6 inhibition to prevent COVID-19 deterioration: more questions than answers
  1. Elizabeth Levy1,
  2. Nuala J Meyer2
  1. 1 Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
  2. 2 Division of Pulmonary, Allergy, and Critical Care Medicine, Center for Translational Lung Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
  1. Correspondence to Dr Nuala J Meyer, Division of Pulmonary, Allergy, and Critical Care Medicine, Center for Translational Lung Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; nuala.meyer{at}pennmedicine.upenn.edu

http://dx.doi.org/10.1136/thorax-2023-220119

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    The COVID-19 pandemic, estimated to have caused at least 6.8 million deaths worldwide,1 highlighted the dearth of effective pharmacotherapy for acute respiratory distress syndrome (ARDS).2 The pandemic also served as a tremendous catalyst for ARDS clinical trials. Faced with an overwhelming number of critically hypoxaemic patients and limited intensive care resources, biopharmaceutical communities rapidly accelerated testing of candidate drugs and the world witnessed an explosion of clinical trials for a syndrome previously with ‘orphan’ status. Whereas some trials concentrated on pathogen-specific aspects of the virus, others focused on ARDS pathogenesis.3 Flooded alveoli are a hallmark of ARDS and there has long been interest in agents that might decrease alveolocapillary permeability. In this issue of Thorax, Ware et al share the results of their randomised control trial investigating a novel antipermeability treatment option for COVID-19.4 Although the trial failed to meet its primary endpoints, important lessons emerge.

    A drug to decrease alveolocapillary permeability has been a Holy Grail for ARDS prevention and treatment5 as prior trials attest (table 1). Transient receptor potential channel C6 (TRPC6) is a novel such target for COVID-19 ARDS. Activation of TRPC6, which occurs in response to stress such as hypoxia, increases the concentration of calcium ions in endothelial cells, causing cell contraction, endothelial cell permeability and pulmonary oedema in mouse models.6 TRPC6 deficient mice did not develop oedema.7 The inhibitor BI 764198 is being actively studied in the treatment of glomerulosclerosis (ClinicalTrials.gov …

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    Footnotes

    • Twitter @elevy323, @nualameyer

    • Contributors EL and NJM wrote and revised the manuscript.

    • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

    • Competing interests NJM reports funding to her institution from the National Institutes of Health and Quantum Leap Healthcare Collaborative. She reports consulting for Endpoint Health and AstraZeneca unrelated to the manuscript topic. EL reports no competing interests.

    • Provenance and peer review Commissioned; externally peer reviewed.

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