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

  • Jinliang Li
    Department of Ophthalmology, Stanford University, Palo Alto, California
  • Shannon C. Kelly
    Department of Biomedical Sciences, University of Missouri, Columbia, Missouri
  • Jan R. Ivey
    Department of Biomedical Sciences, University of Missouri, Columbia, Missouri
  • Pamela K. Thorne
    Department of Biomedical Sciences, University of Missouri, Columbia, Missouri
  • Kelly P. Yamada
    Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York City, New York
  • Tadao Aikawa
    Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York City, New York
  • Renata Mazurek
    Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York City, New York
  • James R. Turk
    Department of Biomedical Sciences, University of Missouri, Columbia, Missouri
  • Kleiton Augusto Santos Silva
    Department of Biomedical Sciences, Cooper Medical School of Rowan University, Camden, New Jersey
  • Amira R. Amin
    Department of Biomedical Sciences, University of Missouri, Columbia, Missouri
  • Darla L. Tharp
    Department of Biomedical Sciences, University of Missouri, Columbia, Missouri
  • Christina M. Mueller
    Department of Biomedical Sciences, University of Missouri, Columbia, Missouri
  • Hrishikesh Thakur
    Department of Ophthalmology, Stanford University, Palo Alto, California
  • Emily V. Leary
    Department of Orthopedic Surgery, University of Missouri, Columbia, Missouri
  • Timothy L. Domeier
    Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, Missouri
  • R. Scott Rector
    Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri
  • Kenneth Fish
    Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York City, New York
  • Federico Cividini
    Cardiac RSK3 Inhibitors, LLC, Los Altos, California
  • Kiyotake Ishikawa
    Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York City, New York
  • Craig A. Emter
    Department of Biomedical Sciences, University of Missouri, Columbia, Missouri
  • Michael S. Kapiloff
    Department of Ophthalmology, Stanford University, Palo Alto, California

抄録

<jats:p> 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 × 10<jats:sup>5</jats:sup> vg/µg genomic DNA (gDNA) for both infusion techniques at a dose ∼10<jats:sup>13</jats:sup> 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. </jats:p>

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