한빛사 논문
Tarik Bozoglu1,2, Seungmin Lee1,2, Tilman Ziegler1,2, Victoria Jurisch1,2, Sanne Maas2,3, Andrea Baehr1,2, Rabea Hinkel1,2,4, Amelie Hoenig1,2, Anjana Hariharan1,2, Christina Inyeop Kim1,2, Simon Decker5, Haider Sami5, Tobias Koppara1,2, Ruppert Oellinger6, Oliver J Müller7, Derk Frank7, Remco Megens3, Peter Nelson8, Christian Weber2,3, Angelika Schnieke9, Markus Sperandio10, Gianluca Santamaria1,2, Roland Rad6, Alessandra Moretti1,2, Karl-Ludwig Laugwitz1,2, Oliver Soehnlein2,3,11, Manfred Ogris5, Christian Kupatt1,2,*
1Klinik und Poliklinik für Innere Medizin I, University Clinic rechts der Isar, Technical University Munich, Germany.
2DZHK (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany.
3Institute for Cardiovascular Prevention, Ludwigs-Maximilians-University, Munich, Germany.
4Deutsches Primatenzentrum GmbH, Leibnitz-Institut für Primatenforschung, Department of Laboratory Animal Science, Göttingen, Germany.
5Faculty of Life Sciences, Department of Pharmaceutical Sciences, Laboratory of MacroMolecular Cancer Therapeutics (MMCT), University of Vienna, Althanstrasse 14, Vienna, 1090, Austria.
6Institute of Molecular Oncology and Functional Genomics, University Clinic rechts der Isar, Technical University of Munic, Germany.
7Klinik für Innere Medizin III and DZHK (German Center for Cardiovascular Research), partner site Hamburg, Kiel, Lübeck., UKSH, Kiel, Germany.
8Medizinische Klinik und Poliklinik IV, Poliklinik Innenstadt, Ludwigs-Maximilians-University, Munich, Germany.
9Department of Animal Sciences, Chair of Livestock Biotechnology, School of Life Sciences Weihenstephan, Technical University Munich, Germany.
10Walter Brendel Centre of Experimental Medicine and Institute of Cardiovascular Physiology and Pathophysiology, BioMedical Centre, Ludwig Maximilians University of Munich, Germany.
11Institute for Experimental Pathology (ExPat), Center for Molecular Biology of Inflammation (ZMBE), WWU Münster, Germany.
T.B., S.L., and T.Z. contributed equally to this study.
*Corresponding author.
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). G2CNN 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 - G2CNN 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 G2CNN AAV9-gRNAs, targeting exons 6–10 of endothelial nitric oxide synthase (eNOS), a vasodilatory enzyme. G2CNN AAV9-Cre transduces microvascular endothelial cells in mTmG-mice or mTmG-pigs. Functionally, G2CNN AAV9-S1FG mediates S1FG-leukocyte adhesion, whereas G2CNN AAV9-Anxa1-application reduces long-term leukocyte recruitment. Moreover, blood pressure increases in Cas9-expressing mice subjected to G2CNN AAV9-gRNAeNOS. Therefore, G2CNN AAV9 may enable gene transfer in vascular and atherosclerosis models.
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