Clin Res Cardiol (2023). https://doi.org/10.1007/s00392-023-02180-w
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Adeno-associated virus serotype 5 is a suitable vector for S100A1-based gene therapy of post-ischemic chronic cardiac dysfunction
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D. Kehr1, J. Salatzki2, B. Krautz1, E. Gao3, K. Varaldi1, J. Birkenstock1, S. Simon1, A. Schneider1, P. Schlegel2, O. J. Müller4, P. Raake5, M. Egger1, W. Koch3, J. Riffel2, F. André2, H. A. Katus2, N. Frey2, A. Jungmann1, M. Busch1, H. Pfannkuche6, P. Most1
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1Innere Medizin III, Inst. für Molekulare und Translationale Kardiologie, Universitätsklinikum Heidelberg, Heidelberg; 2Klinik für Innere Med. III, Kardiologie, Angiologie u. Pneumologie, Universitätsklinikum Heidelberg, Heidelberg; 3Center for Translational Medicine, Temple University Philadelphia, Philadelphia, US; 4Klinik für Innere Medizin III, Schwerpunkt Kardiologie und Angiologie, Universitätsklinikum Schleswig-Holstein, Kiel; 5I. Medizinische Klinik, Universitätsklinikum Augsburg, Augsburg; 6Institute of Veterinary Physiology, Faculty of Veterinary Medicine, Leipzig;
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Introduction: 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.
Hypothesis: 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.
Methods: 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
Results: In a comparative study of AAV5-, 6- and 9-luciferase (luc) in healthy
farm pigs (n=5 each; 1x1013 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 study, we demonstrated a
significant improvement in EF (+19 ± 5 %) 12 weeks after retrograde AAV5-S100A1
gene delivery compared to AAV5-luc in infarcted pigs (n=4 each; 1x1013
vgc/pig). Moreover, S100A1-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. S100A1 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 2×1011 vgc of AAV5-S100A1 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.
Conclusion: 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
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https://dgk.org/kongress_programme/jt2023/aP1773.html
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