Abstract P2104: Adeno-associated Virus Serotype 5 Is A Suitable Vector For S100a1-based Gene Therapy Of Post-ischemic Chronic Cardiac Dysfunction

Media type: E-Article
Title: Abstract P2104: Adeno-associated Virus Serotype 5 Is A Suitable Vector For S100a1-based Gene Therapy Of Post-ischemic Chronic Cardiac Dysfunction
Contributor: Kehr, Dorothea; Salatzki, Janek; Krautz, Birgit; Gao, Erhe; Varadi, Karl; Birkenstock, Jennifer; Schlegel, Philipp; Müller, Oliver; Raake, Philip W; Egger, Michael; Koch, Walter J; Riffel, Johannes; André, Florian; Katus, Hugo A; Frey, Norbert; Jungmann, Andreas; Busch, Martin; Pfannkuche, Helga; Most, Patrick
Published: Ovid Technologies (Wolters Kluwer Health), 2022
Published in: Circulation Research, 131 (2022) Suppl_1
Language: English
DOI: 10.1161/res.131.suppl_1.p2104
ISSN: 1524-4571; 0009-7330
Keywords: Cardiology and Cardiovascular Medicine ; Physiology
Origination:
Footnote:
Description: <jats:p> <jats:bold>Introduction:</jats:bold> For S100A1-based heart failure gene therapies, AAV9 and 6 have shown efficacy in pre-clinical large animal studies. As AAV9 has shown concerning signs of toxicity in clinical studies and AAV6 displays poor production yields, there is need for a novel safe and cardiac-specific AAV serotype. </jats:p> <jats:p> <jats:bold>Hypothesis:</jats:bold> We hypothesized that in a pig model the safety proven and scalably manufacturable AAV5 may be a suitable vector for S100A1-based gene therapy of post-ischemic cardiac dysfunction. </jats:p> <jats:p> <jats:bold>Methods:</jats:bold> AAV production, 2h balloon-occlusion of the LCX, retrograde cardiac gene delivery, cardiac MRI, late gadolinium enhancement (LGE), global T1 relaxation, qPCR, RNA-Seq, WGCNA, KEGG, Reactome, LAD-ligation mouse model </jats:p> <jats:p> <jats:bold>Results:</jats:bold> In a comparative study of AAV5-, 6- and 9-luciferase (luc) in healthy farm pigs (n=5 each; 1x10 <jats:sup>13</jats:sup> vgc/pig), AAV5 achieved a more homogeneous cardiac apical-basal transduction pattern than AAV6 with a higher luc activity than AAV9. In a clinically relevant endpoint driven study, we demonstrated a significant improvement in EF (+19 ± 5 %) 12 weeks after retrograde AAV5- <jats:italic>S100A1</jats:italic> gene delivery compared to AAV5-luc in infarcted pigs (n=4 each; 1x10 <jats:sup>13</jats:sup> vgc/pig). Moreover, <jats:italic>S100A1</jats:italic> -treated pigs showed significantly less infarct extension (-0.5 ± 0.3 g vs. 5 ± 1.3 g (luc)) measured by cardiac MRI. There were no unfavorable alterations in blood chemistry or ECG. <jats:italic>S100A1</jats:italic> expression was predominantly contained to the heart. The WGCNA unveiled a significant correlation between the improved EF and a suppression of inflammatory and immunological pathways (r=-0.96, p < 0.01) and between the absent infarct extension and enhanced activity of cardioprotective signaling (r=-0.82, p < 0.05). With injections of 2х10 <jats:sup>11</jats:sup> vgc of AAV5- <jats:italic>S100A1</jats:italic> or AAV5-gfp (n=4 each) into the remote myocardium in the mouse model, we confirmed a significant improvement in FS (+43.8 ± 8.8 %, vs. gfp) and suppression of inflammatory gene expression including i.e., IL1b or TNFa by S100A1. </jats:p> <jats:p> <jats:bold>Conclusion:</jats:bold> We conclude that AAV5 is suitable for S100A1-based gene therapy of post-ischemic cardiac dysfunction and that this vector/target combination can help accelerating the way towards a clinical trial. We also found novel signaling pathways that may be involved in S100A1’s therapeutic actions. </jats:p>
Access State: Open Access

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