Endothelial Retargeting of AAV9 In Vivo

Bozoglu, Tarik; Lee, Seungmin; Ziegler, Tilman; Jurisch, Victoria; Maas, Sanne; Baehr, Andrea; Hinkel, Rabea; Hoenig, Amelie; Hariharan, Anjana; Kim, Christina Inyeop; Decker, Simon; Sami, Haider; Koppara, Tobias; Oellinger, Ruppert; Müller, Oliver J.; Frank, Derk; Megens, Remco; Nelson, Peter; Weber, Christian; Schnieke, Angelika; Sperandio, Markus; Santamaria, Gianluca; Rad, Roland; Moretti, Alessandra; Laugwitz, Karl-Ludwig; Soehnlein, Oliver; Ogris, Manfred und Kupatt, Christian (2022): Endothelial Retargeting of AAV9 In Vivo. In: Advanced Science, Bd. 9, Nr. 7, 2103867

Abstract

Adeno-associated viruses (AAVs) are frequently used for gene transfer and gene editing in vivo, except for endothelial cells, which are remarkably resistant to unmodified AAV-transduction. AAVs are retargeted here toward endothelial cells by coating with second-generation polyamidoamine dendrimers (G2) linked to endothelial-affine peptides (CNN). G2(CNN) AAV9-Cre (encoding Cre recombinase) are injected into mTmG-mice or mTmG-pigs, cell-specifically converting red to green fluorescence upon Cre-activity. Three endothelial-specific functions are assessed: in vivo quantification of adherent leukocytes after systemic injection of - G2(CNN) AAV9 encoding 1) an artificial adhesion molecule (S1FG) in wildtype mice (day 10) or 2) anti-inflammatory Annexin A1 (Anxa1) in ApoE(-/-) mice (day 28). Moreover, 3) in Cas9-transgenic mice, blood pressure is monitored till day 56 after systemic application of G2(CNN) AAV9-gRNAs, targeting exons 6-10 of endothelial nitric oxide synthase (eNOS), a vasodilatory enzyme. G2(CNN) AAV9-Cre transduces microvascular endothelial cells in mTmG-mice or mTmG-pigs. Functionally, G2(CNN) AAV9-S1FG mediates S1FG-leukocyte adhesion, whereas G2(CNN) AAV9-Anxa1-application reduces long-term leukocyte recruitment. Moreover, blood pressure increases in Cas9-expressing mice subjected to G2(CNN) AAV9-gRNA(eNOS). Therefore, G2(CNN) AAV9 may enable gene transfer in vascular and atherosclerosis models.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 213602983
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 403584255
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 238187445