Biological pacemaker induced by focal cardiac transduction with AAV-TBX18

When injected into the heart, adenovirally packaged T-box transcription factor 18 (TBX18) induces biological pacemaker activity, but immunological clearance of transduced cells limits efficacy. Here, we investigated whether expressing TBX18 in the less inflammatory adeno-associated virus (AAV-TBX18) represents a viable alternative. Focal injection of AAV-TBX18 (but not a control AAV expressing green fluorescent protein [AAV-GFP]) in the left ventricle of rats altered local gene expression to resemble that of the sinoatrial node and unleashed automaticity originating at the site of injection. AAV-TBX18-induced pacemakers exhibited autonomic responsiveness, while increasing maximal exercise tolerance. Likewise, catheter-based delivery of AAV-TBX18 (but not AAV-GFP) into the His bundle region in pigs increased heart rate in a clinically relevant porcine model of complete atrioventricular block. The heart rate remained significantly higher in AAV-TBX18 animals than in AAV-GFP controls for at least 6 weeks in rats and 4 weeks in pigs. Thus, targeted intramyocardial injection of AAV-TBX18 induces durable, physiologically responsive chronotropic support in both rats and pigs with complete heart block.