Distribution of cardiomyocyte-selective adeno-associated virus serotype 9 vectors in swine following intracoronary and intravenous infusion
Abstract
Limited reports exist regarding adeno-associated virus (AAV) biodistribution in swine. This study assessed biodistribution following antegrade intracoronary and intravenous delivery of two self-complementary serotype 9 AAV (AAV9sc) biologics designed to target signaling in the cardiomyocyte considered important for the development of heart failure. Under the control of a cardiomyocyte-specific promoter, AAV9sc.shmAKAP and AAV9sc.RBD express a small hairpin RNA for the perinuclear scaffold protein muscle A-kinase anchoring protein β (mAKAPβ) 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 × 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 moderately 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 indicate 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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jul 01, 2022
- Source ID
- 10.1152/physiolgenomics.00032.2022
Entities
People
- Amira R. Amin
- Christina M. Mueller
- Craig A Emter
- Darla L. Tharp
- Emily Leary
- Federico Cividini
- Hrishikesh Thakur
- James R. Turk
- Jan R. Ivey
- Jinliang Li
- Kelly P. Yamada
- Kenneth Fish
- Kiyotake Ishikawa
- Kleiton Augusto dos Santos Silva
- Michael S Kapiloff
- Pamela K. Thorne
- R. Scott Rector
- Renata Mazurek
- Shannon C. Kelly
- Tadao Aikawa
- Timothy L. Domeier
Organizations
- Icahn School of Medicine at Mount Sinai
- National Heart, Lung, and Blood Institute
- Rowan University
- Stanford University
- United States Department of Defense
- University of Missouri