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; Stefan Engelhardt

doi:10.1038/s41467-023-40185-1

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, Stefan Engelhardt

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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.

Original language	English
Article number	4564
Journal	Nature Communications
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41467-023-40185-1
State	Published - Dec 2023

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Beck, C., Ramanujam, D., Vaccarello, P., Widenmeyer, F., Feuerherd, M., Cheng, C. C., Bomhard, A., Abikeeva, T., Schädler, J., Sperhake, J. P., Graw, M., Safi, S., Hoffmann, H., Staab-Weijnitz, C. A., Rad, R., Protzer, U., Frischmuth, T., & Engelhardt, S. (2023). Trimannose-coupled antimiR-21 for macrophage-targeted inhalation treatment of acute inflammatory lung damage. Nature Communications, 14(1), Article 4564. https://doi.org/10.1038/s41467-023-40185-1

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title = "Trimannose-coupled antimiR-21 for macrophage-targeted inhalation treatment of acute inflammatory lung damage",

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.",

author = "Christina Beck and Deepak Ramanujam and Paula Vaccarello and Florenc Widenmeyer and Martin Feuerherd and Cheng, {Cho Chin} and Anton Bomhard and Tatiana Abikeeva and Julia Sch{\"a}dler and Sperhake, {Jan Peter} and Matthias Graw and Seyer Safi and Hans Hoffmann and Staab-Weijnitz, {Claudia A.} and Roland Rad and Ulrike Protzer and Thomas Frischmuth and Stefan Engelhardt",

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Beck, C, Ramanujam, D, Vaccarello, P, Widenmeyer, F, Feuerherd, M, Cheng, CC, Bomhard, A, Abikeeva, T, Schädler, J, Sperhake, JP, Graw, M, Safi, S, Hoffmann, H, Staab-Weijnitz, CA, Rad, R , Protzer, U, Frischmuth, T & Engelhardt, S 2023, 'Trimannose-coupled antimiR-21 for macrophage-targeted inhalation treatment of acute inflammatory lung damage', Nature Communications, vol. 14, no. 1, 4564. https://doi.org/10.1038/s41467-023-40185-1

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AU - Beck, Christina

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AU - Vaccarello, Paula

AU - Widenmeyer, Florenc

AU - Feuerherd, Martin

AU - Cheng, Cho Chin

AU - Bomhard, Anton

AU - Abikeeva, Tatiana

AU - Schädler, Julia

AU - Sperhake, Jan Peter

AU - Graw, Matthias

AU - Safi, Seyer

AU - Hoffmann, Hans

AU - Staab-Weijnitz, Claudia A.

AU - Rad, Roland

AU - Protzer, Ulrike

AU - Frischmuth, Thomas

AU - Engelhardt, Stefan

PY - 2023/12

Y1 - 2023/12

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AB - 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.

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

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