Distribution of cardiomyocyte-selective adeno-associated virus serotype 9 vectors in swine following intracoronary and intravenous infusion

Limited reports exist regarding adeno-associated virus (AAV) biodistribution in swine. This study assessed biodistribution follow- ing antegrade intracoronary and intravenous delivery of two self-complementary serotype 9 AAV (AAV9sc) biologies designed to target signaling in the cardiomyocyte considered important for the development of heart failure. Under the control of a cardiomy- ocyte-specific promoter, AAV9sc.shmAKAP and AAV9sc.RBD express a small hairpin RNA for the perinuclear scaffold protein muscle A-kinase anchoring protein ß (mAKAPß) and an anchoring disruptor peptide for p90 ribosomal S6 kinase type 3 (RSK3), respectively. Quantitative PCR was used to assess viral genome (vg) delivery and transcript expression in Ossabaw and Yorkshire swine tissues. Myocardial viral delivery was 2-5 x 105 vg/μg genomic DNA (gDNA) for both infusion techniques at a dose ~1013 vg/kg body wt, demonstrating delivery of ~1-3 viral particles per cardiac diploid genome. Myocardial RNA levels for each expressed transgene were generally proportional to dose and genomic delivery, and comparable with levels for moder- ately expressed endogenous genes. Despite significant AAV9sc delivery to other tissues, including the liver, neither biologic induced toxic effects as assessed using functional, structural, and circulating cardiac and systemic markers. These results indi- cate successful targeted delivery of cardiomyocyte-selective viral vectors in swine without negative side effects, an important step in establishing efficacy in a preclinical experimental setting.