Cationic LNP-formulated mRNA expressing Tie2-agonist in the lung endothelium prevents pulmonary vascular leakage

Katrin Radloff; Birgitt Gutbier; Charlotte Maeve Dunne; Hanieh Moradian; Marko Schwestka; Manfred Gossen; Katharina Ahrens; Laura Kneller; Yadong Wang; Akanksha Moga; Leonidas Gkionis; Oliver Keil; Volker Fehring; Daniel Tondera; Klaus Giese; Ansgar Santel; Jörg Kaufmann; Martin Witzenrath

doi:10.1016/j.omtn.2023.102068

Cationic LNP-formulated mRNA expressing Tie2-agonist in the lung endothelium prevents pulmonary vascular leakage

Mol Ther Nucleic Acids. 2023 Oct 29:34:102068. doi: 10.1016/j.omtn.2023.102068. eCollection 2023 Dec 12.

Authors

Katrin Radloff¹, Birgitt Gutbier², Charlotte Maeve Dunne¹, Hanieh Moradian^{3

4}, Marko Schwestka^{3

4}, Manfred Gossen^{3

4}, Katharina Ahrens², Laura Kneller², Yadong Wang², Akanksha Moga¹, Leonidas Gkionis¹, Oliver Keil¹, Volker Fehring¹, Daniel Tondera¹, Klaus Giese¹, Ansgar Santel¹, Jörg Kaufmann¹, Martin Witzenrath²

Affiliations

¹ Pantherna Therapeutics GmbH, 16761 Hennigsdorf, Germany.
² Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Infectious Diseases, Respiratory Medicine, and Critical Care, 10117 Berlin, Germany.
³ Institute of Active Polymers, Helmholtz-Zentrum Hereon, 14513 Teltow, Germany.
⁴ Berlin-Brandenburg Center for Regenerative Therapies (BCRT) Charité Campus Virchow Klinikum, 13353 Berlin, Germany.

Abstract

Dysfunction of endothelial cells (ECs) lining the inner surface of blood vessels are causative for a number of diseases. Hence, the ability to therapeutically modulate gene expression within ECs is of high therapeutic value in treating diseases such as those associated with lung edema. mRNAs formulated with lipid nanoparticles (LNPs) have emerged as a new drug modality to induce transient protein expression for modulating disease-relevant signal transduction pathways. In the study presented here, we tested the effect of a novel synthetic, nucleoside-modified mRNA encoding COMP-Ang1 (mRNA-76) formulated into a cationic LNP on attenuating inflammation-induced vascular leakage. After intravenous injection, the respective mRNA was found to be delivered almost exclusively to the ECs of the lung, while sparing other vascular beds and bypassing the liver. The mode of action of mRNA-76, such as its activation of the Tie2 signal transduction pathway, was tested by pharmacological studies in vitro and in vivo in respective mouse models. mRNA-76 was found to prevent lung vascular leakage/lung edema as well as neutrophil infiltration in a lipopolysaccharide-challenging model.

Keywords: ARDS; MT: Oligonucleotides: Therapies and Applications; acute respiratory distress syndrome; cationic lipid nanoparticles; edema; endothelium; mRNA; therapeutic modulation of gene expression; tissue-specific targeting of the lung vasculature.