Cardiac-targeted AAV5-S100A1 gene therapy protects against adverse remodeling and contractile dysfunction in post-ischemic herats
Background: Guided by long-term safety data for AAV5 in humans, our translational study investigated whether AAV5 effectively delivers genes to healthy and achieve therapeutic efficacy in dysfunctional human-sized hearts, using a clinically applicable mode of administration and vector dosages. Methods & Results: In a first biodistribution study, AAV5 (1?1013 vector genomes; vgs) - carrying the reporter gene luciferase (luc) - achieved broad and homogenous transduction of the left ventricle (LV) of healthy German farm pigs 30 days after percutaneous catheter-based retrograde intravenous delivery (CRID), as measured by vector genome and luc mRNA assessments. Both its myocardial and extra-cardiac distribution patterns were advantageous compared to AAV9-luc and AAV6-luc. Using the cardioprotective human gene S100A1 (hS100A1) in a subsequent therapy study, effective myocardial transduction with AAV5-hS100A1 (1?1013 vgcs) by CRID prevented LV myocardial infarction (MI) enlargement and improved systolic contractile performance after 3 months in a porcine model with chronic post-MI cardiac dysfunction, as assessed by serial cardiac magnetic resonance imaging. The use of a cardiac-biased promoter ensured cardiac-targeted hS100A1 expression without signs of clinical toxicity, as shown by RT-PCR analysis, clinical chemistry and blood count. A previously unknown anti-inflammatory effect of hS100A1 in damaged myocardium, detected and linked to the therapeutic actions by a cardiac transcriptome weighted gene coexpression network analysis, was confirmed using AAV5-hS100A1 therapy in a post-MI mouse model, as measured by RT-PCR and echocardiography. Conclusion: 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 as well as low pre-existing immunity in humans may predestine AAV5 as an effective and safe gene carrier for a prevalent disease as chronic heart failure, using therapeutic genetic effectors, such as hS100A1 or others. Overall design: RNA-seq, WGCNA and enrichment analysis of myocardial tissue (anteromidventricular) of male farm pigs 14 weeks after LCX-myocardial infarction, AAV5-hS100A1 treated vs. AAV5-luc