Cardiac-targeted AAV5-S100A1 gene therapy protects against adverse remodeling and contractile dysfunction in postischemic hearts
BACKGROUND: - Guided by long-term safety data for AAV5 (adeno-associated virus 5) in humans, our translational study investigated whether AAV5 effectively delivers genes to healthy and achieves therapeutic efficacy in dysfunctional human-sized hearts, using a clinically applicable mode of administra...
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| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
19 June 2025
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| In: |
Circulation. Heart failure
Year: 2025, Volume: 18, Issue: 7, Pages: 1-14 |
| ISSN: | 1941-3297 |
| DOI: | 10.1161/CIRCHEARTFAILURE.124.012479 |
| Online Access: | Verlag, kostenfrei, Volltext: https://doi.org/10.1161/CIRCHEARTFAILURE.124.012479 Verlag, kostenfrei, Volltext: https://www.ahajournals.org/doi/10.1161/CIRCHEARTFAILURE.124.012479 
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| Author Notes: | Dorothea Kehr, DVM; Janek Salatzki, MD; Birgit Seger, DVM; Karl Varadi, PhD; Jennifer Birkenstock; Philipp Schlegel, MD; Erhe Gao, MD, PhD; Walter J. Koch, PhD; Hugo A. Katus, MD; Norbert Frey, MD; Johannes Riffel, MD; Florian André, MD;Karsten Peppel, PhD; Andreas Jungmann, PhD; Martin Busch, PhD; Helga Pfannkuche, DVM; Julia Ritterhoff, PhD; Patrick Most, MD |
| Summary: | BACKGROUND: - Guided by long-term safety data for AAV5 (adeno-associated virus 5) in humans, our translational study investigated whether AAV5 effectively delivers genes to healthy and achieves therapeutic efficacy in dysfunctional human-sized hearts, using a clinically applicable mode of administration and vector dosages. - METHODS: - AAV-mediated cardiac gene transfer in pigs was performed by percutaneous catheter-based retrograde intravenous vector delivery, and vector genome and transgene expression levels determined by reverse transcription-polymerase chain reaction and immunoblotting. Postmyocardial infarction (MI) cardiac dysfunction porcine and murine models were generated by coronary catheter-based occlusion and ligation, respectively. The study end points left ventricular ejection fraction and left ventricular MI size, were measured by cardiac magnetic resonance imaging and echocardiography. Bulk myocardial RNA-sequencing and weighted gene correlation network analysis were used to link study end points to molecular pathway mechanisms. Safety was assessed by clinical chemistry, blood count and ECG. - RESULTS: - In a first biodistribution study, AAV5 (1×1013 vector genomes; vgs) with the reporter gene luciferase (luc) achieved broad and homogenous transduction of healthy pig hearts 30 days after catheter-based retrograde intravenous vector delivery without toxicity. Both its myocardial and extra-cardiac distribution patterns were advantageous compared with AAV9-luc and AAV6-luc. Using AAV5 with the cardioprotective human gene S100A1 (hS100A1; 1×1013 vgcs) by catheter-based retrograde intravenous vector delivery in a subsequent therapy study in post-MI pigs prevented left ventricular MI extension and improved left ventricular ejection fraction after 3 months without clinical toxicity. Weighted gene correlation network analysis linked novel antiinflammatory actions and cardioprotective signaling mechanisms by hS100A1 to study end point improvements, which was confirmed in a post-MI mouse model. - CONCLUSIONS: - Providing the clinically relevant proof of concept for AAV5 to effectively transduce healthy and dysfunctional human-sized hearts, its clinical long-term safety, scalable producibility, and low preexisting immunity in humans may predestine AAV5 as an effective and safe gene carrier for a prevalent disease such as chronic heart failure, using therapeutic genetic effectors such as hS100A1 or others. |
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| Item Description: | Gesehen am 15.12.2025 |
| Physical Description: | Online Resource |
| ISSN: | 1941-3297 |
| DOI: | 10.1161/CIRCHEARTFAILURE.124.012479 |