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

Christina Beck, Deepak Ramanujam, Paula Vaccarello, Florenc Widenmeyer, Martin Feuerherd, Cho-Chin Cheng, Anton Bomhard, Tatiana Abikeeva, Julia Schädler, Jan-Peter Sperhake, Matthias Graw, Seyer Safi, Hans Hoffmann, Claudia A. Staab-Weijnitz, Roland Rad, Ulrike Protzer, Thomas Frischmuth and Stefan Engelhardt ()
Additional contact information
Christina Beck: Technical University of Munich (TUM)
Deepak Ramanujam: Technical University of Munich (TUM)
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
Thomas Frischmuth: Baseclick GmbH
Stefan Engelhardt: Technical University of Munich (TUM)

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-40185-1

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