Cardiac-targeted rAAV5-S100A1 gene therapy protects against adverse remodeling and contractile dysfunction in post-ischemic hearts

Toxicity by recombinant adeno-associated viruses (rAAV) in clinical gene therapy trials (e.g., by rAAV9-mediated fatal liver failure) significantly impairs translation of preclinical rAAV-based cardiac gene therapies employing these vectors. For rAAV5 - a capsid that has shown long-term safety in clinical trials - our translational study demonstrates effective transduction of the left ventricle (LV) of healthy pigs via catheter-based retrograde intravenous delivery (CRID) by means of luciferase reporter gene biodistribution analyses. Combination of rAAV5 with the cardioprotective human gene S100A1 ( hS100A1 ) prevents LV myocardial infarct (MI) enlargement and improves LV systolic contractile performance in a porcine model of post-MI chronic cardiac dysfunction. Use of a cardiac-biased promoter ensured the cardiac-directed expression of the therapeutic human transgene without signs of clinical toxicity. The beneficial effects of rAAV5- hS100A1 were linked to an attenuated activity of post-MI inflammatory gene networks and this was further validated in a murine model. These novel data together with proven scalable producibility and low pre-existing immunity against rAAV5 in humans may collectively advance clinical translation of rAAV5- hS100A1 as a gene therapy medicinal product (GTMP) for a common cardiovascular disease, such as chronic heart failure (CHF). Highlights ### Competing Interest Statement The authors have declared no competing interest. * AAV : Adeno-associated virus CMR : Cardiac magnetic resonance CRID : Catheter-based retrograde cardiac-targeted intravenous delivery CUPID : Calcium upregulation by percutaneous administration of gene therapy in patients with cardiac diseases CHF : Congestive heart failure FAEs : Fatal adverse events GTMP : Gene therapy medicinal product GFP : Green fluorescent protein IND : Investigational new drug LGE : Late gadolinium enhancement LAD : Left anterior descending artery LCX : Left circumflex artery LVEF : Left ventricular ejection fraction luc : Luciferase ME : Module eigengene MI : Myocardial infarction MLCv2 : Myosin light chain ventricle-2 ROA : Route of administration SAEs : Serious adverse events vgcs : Vector genome copies WGCNA : Weighted gene co-expression network analysis