Abstract 18864: A Novel Technique to Improve Vector Uptake for Cardiac Gene Therapy

Abstract

Introduction: Cardiac gene therapy with adeno-associated virus (AAV) has promise. However, clinical trials with intracoronary (IC) delivery have been challenged by low efficacy. Hypothesis: We predicted that AAV uptake could be enhanced using a catheter-based mechanical cardiac support device (MCS) to facilitate IC delivery with brief coronary balloon occlusions in a pig model of myocardial infarction (MI). Aims: We aimed to: 1) confirm that MCS could support hemodynamics during coronary balloon occlusions, and 2) determine whether this technique could improve vector uptake and cardiac gene expression after HF onset. Methods: A week after MI, 12 Yorkshire pigs (36.6±1.45 kg, male n=6) received AAV6 encoding for luciferase by one of four delivery methods (n=3/group) (Figure 1). Tissues were harvested 1 mo later for analysis. A similar experiment was conducted with gold nanoparticles (GNPs) in place of AAV by either continuous or CAO+CSO delivery (n=4) with same-day cardiac harvest. GNP presence was seen by electron microscopy. Results: MCS maintained blood pressure and prevented arrhythmias during coronary balloon occlusions. Application of MCS during continuous infusion did not significantly alter AAV genome uptake (vg) or luciferase expression (luc). CAO+CSO delivery increased both vg and luc across heart regions, with notable significance at the infarct-border region vs continuous delivery (vg: p=0.027; luc: p=0.032). Vg was also positively associated with luc (Figure 2). Improved uptake was further supported by greater GNP presence with CAO+CSO delivery. Conclusion: MCS can be utilized to optimize IC gene delivery in a safe and clinically-applicable way.