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

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 formula...

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Autores principales: Radloff, Katrin, Gutbier, Birgitt, Dunne, Charlotte Maeve, Moradian, Hanieh, Schwestka, Marko, Gossen, Manfred, Ahrens, Katharina, Kneller, Laura, Wang, Yadong, Moga, Akanksha, Gkionis, Leonidas, Keil, Oliver, Fehring, Volker, Tondera, Daniel, Giese, Klaus, Santel, Ansgar, Kaufmann, Jörg, Witzenrath, Martin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society of Gene & Cell Therapy 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10682670/
https://www.ncbi.nlm.nih.gov/pubmed/38034031
http://dx.doi.org/10.1016/j.omtn.2023.102068
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author Radloff, Katrin
Gutbier, Birgitt
Dunne, Charlotte Maeve
Moradian, Hanieh
Schwestka, Marko
Gossen, Manfred
Ahrens, Katharina
Kneller, Laura
Wang, Yadong
Moga, Akanksha
Gkionis, Leonidas
Keil, Oliver
Fehring, Volker
Tondera, Daniel
Giese, Klaus
Santel, Ansgar
Kaufmann, Jörg
Witzenrath, Martin
author_facet Radloff, Katrin
Gutbier, Birgitt
Dunne, Charlotte Maeve
Moradian, Hanieh
Schwestka, Marko
Gossen, Manfred
Ahrens, Katharina
Kneller, Laura
Wang, Yadong
Moga, Akanksha
Gkionis, Leonidas
Keil, Oliver
Fehring, Volker
Tondera, Daniel
Giese, Klaus
Santel, Ansgar
Kaufmann, Jörg
Witzenrath, Martin
author_sort Radloff, Katrin
collection PubMed
description 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.
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spelling pubmed-106826702023-11-30 Cationic LNP-formulated mRNA expressing Tie2-agonist in the lung endothelium prevents pulmonary vascular leakage Radloff, Katrin Gutbier, Birgitt Dunne, Charlotte Maeve Moradian, Hanieh Schwestka, Marko Gossen, Manfred Ahrens, Katharina Kneller, Laura Wang, Yadong Moga, Akanksha Gkionis, Leonidas Keil, Oliver Fehring, Volker Tondera, Daniel Giese, Klaus Santel, Ansgar Kaufmann, Jörg Witzenrath, Martin Mol Ther Nucleic Acids Original Article 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. American Society of Gene & Cell Therapy 2023-10-29 /pmc/articles/PMC10682670/ /pubmed/38034031 http://dx.doi.org/10.1016/j.omtn.2023.102068 Text en © 2023 The Author(s) https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Original Article
Radloff, Katrin
Gutbier, Birgitt
Dunne, Charlotte Maeve
Moradian, Hanieh
Schwestka, Marko
Gossen, Manfred
Ahrens, Katharina
Kneller, Laura
Wang, Yadong
Moga, Akanksha
Gkionis, Leonidas
Keil, Oliver
Fehring, Volker
Tondera, Daniel
Giese, Klaus
Santel, Ansgar
Kaufmann, Jörg
Witzenrath, Martin
Cationic LNP-formulated mRNA expressing Tie2-agonist in the lung endothelium prevents pulmonary vascular leakage
title Cationic LNP-formulated mRNA expressing Tie2-agonist in the lung endothelium prevents pulmonary vascular leakage
title_full Cationic LNP-formulated mRNA expressing Tie2-agonist in the lung endothelium prevents pulmonary vascular leakage
title_fullStr Cationic LNP-formulated mRNA expressing Tie2-agonist in the lung endothelium prevents pulmonary vascular leakage
title_full_unstemmed Cationic LNP-formulated mRNA expressing Tie2-agonist in the lung endothelium prevents pulmonary vascular leakage
title_short Cationic LNP-formulated mRNA expressing Tie2-agonist in the lung endothelium prevents pulmonary vascular leakage
title_sort cationic lnp-formulated mrna expressing tie2-agonist in the lung endothelium prevents pulmonary vascular leakage
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10682670/
https://www.ncbi.nlm.nih.gov/pubmed/38034031
http://dx.doi.org/10.1016/j.omtn.2023.102068
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