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Updated: Sep 19, 2025
Gene Transfer for Ischemic Heart Failure in a Preclinical Model
Published on: May 15, 2011
Cardiac-Targeted AAV5-S100A1 Gene Therapy Protects Against Adverse Remodeling and Contractile Dysfunction in
Dorothea Kehr1,2,3, Janek Salatzki2, Birgit Seger1,2
1Division of Molecular and Translational Cardiology (D.K., B.S., K.V., J.B., A.J., M.B., J. Ritterhoff, P.M.), University Hospital Heidelberg, Germany.
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.
