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Trimannose-coupled antimiR-21 for macrophage-targeted inhalation treatment of acute inflammatory lung damage

Author

Listed:
  • Christina Beck

    (Technical University of Munich (TUM)
    partner site Munich Heart Alliance)

  • Deepak Ramanujam

    (Technical University of Munich (TUM)
    partner site Munich Heart Alliance
    RNATICS GmbH)

  • Paula Vaccarello

    (Technical University of Munich (TUM))

  • Florenc Widenmeyer

    (Technical University of Munich (TUM))

  • Martin Feuerherd

    (Technical University of Munich (TUM), School of Medicine)

  • Cho-Chin Cheng

    (Technical University of Munich (TUM), School of Medicine)

  • Anton Bomhard

    (Technical University of Munich (TUM))

  • Tatiana Abikeeva

    (Technical University of Munich (TUM))

  • Julia Schädler

    (University Medical Center Hamburg-Eppendorf)

  • Jan-Peter Sperhake

    (University Medical Center Hamburg-Eppendorf)

  • Matthias Graw

    (Ludwig-Maximilians-Universität (LMU) München)

  • Seyer Safi

    (Klinikum rechts der Isar, Technical University of Munich (TUM))

  • Hans Hoffmann

    (Klinikum rechts der Isar, Technical University of Munich (TUM))

  • Claudia A. Staab-Weijnitz

    (Helmholtz Center Munich, Member of the German Center of Lung Research (DZL))

  • Roland Rad

    (Technical University of Munich (TUM))

  • Ulrike Protzer

    (Technical University of Munich (TUM), School of Medicine
    partner site Munich)

  • Thomas Frischmuth

    (Baseclick GmbH
    RNATICS GmbH)

  • Stefan Engelhardt

    (Technical University of Munich (TUM)
    partner site Munich Heart Alliance)

Abstract

Recent studies of severe acute inflammatory lung disease including COVID-19 identify macrophages to drive pulmonary hyperinflammation and long-term damage such as fibrosis. Here, we report on the development of a first-in-class, carbohydrate-coupled inhibitor of microRNA-21 (RCS-21), as a therapeutic means against pulmonary hyperinflammation and fibrosis. MicroRNA-21 is among the strongest upregulated microRNAs in human COVID-19 and in mice with acute inflammatory lung damage, and it is the strongest expressed microRNA in pulmonary macrophages. Chemical linkage of a microRNA-21 inhibitor to trimannose achieves rapid and specific delivery to macrophages upon inhalation in mice. RCS-21 reverses pathological activation of macrophages and prevents pulmonary dysfunction and fibrosis after acute lung damage in mice. In human lung tissue infected with SARS-CoV-2 ex vivo, RCS-21 effectively prevents the exaggerated inflammatory response. Our data imply trimannose-coupling for effective and selective delivery of inhaled oligonucleotides to pulmonary macrophages and report on a first mannose-coupled candidate therapeutic for COVID-19.

Suggested Citation

  • Christina Beck & Deepak Ramanujam & Paula Vaccarello & Florenc Widenmeyer & Martin Feuerherd & Cho-Chin Cheng & Anton Bomhard & Tatiana Abikeeva & Julia Schädler & Jan-Peter Sperhake & Matthias Graw &, 2023. "Trimannose-coupled antimiR-21 for macrophage-targeted inhalation treatment of acute inflammatory lung damage," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40185-1
    DOI: 10.1038/s41467-023-40185-1
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    as
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