Endothelial Retargeting of AAV9 In Vivo

Bozoglu T, Lee S, Ziegler T, Jurisch V, Maas S, Baehr A, Hinkel R, Hoenig A, Hariharan A, Kim CI, Decker S, Sami H, Koppara T, Oellinger R, Muller OJ, Frank D, Megens R, Nelson P, Weber C, Schnieke A, Sperandio M, Santamaria G, Rad R, Moretti A, Laugwitz KL, Soehnlein O, Ogris M, Kupatt C (2022)

Publication Type: Journal article

Publication year: 2022

Journal

Advanced Science Wiley Open Access

Book Volume: 9

Article Number: 2103867

Journal Issue: 7

DOI: 10.1002/advs.202103867

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.

Involved external institutions

Technische Universität München (TUM)

Germany (DE) Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK e.V.)

Germany (DE) Universität Wien / University of Vienna

Austria (AT) Universitätsklinikum Schleswig-Holstein (UKSH)

Germany (DE) Ludwig-Maximilians-Universität (LMU)

Germany (DE)

How to cite

APA:

Bozoglu, T., Lee, S., Ziegler, T., Jurisch, V., Maas, S., Baehr, A.,... Kupatt, C. (2022). Endothelial Retargeting of AAV9 In Vivo. Advanced Science, 9(7). https://doi.org/10.1002/advs.202103867

MLA:

Bozoglu, Tarik, et al. "Endothelial Retargeting of AAV9 In Vivo." Advanced Science 9.7 (2022).

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