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(Circulation Research. 2006;99:e3.)
© 2006 American Heart Association, Inc.

UltraRapid Communication

Recombinant Adeno-Associated Virus Serotype 9 Leads to Preferential Cardiac Transduction In Vivo

Christina A. Pacak, Cathryn S. Mah, Bijoy D. Thattaliyath, Thomas J. Conlon, Melissa A. Lewis, Denise E. Cloutier, Irene Zolotukhin, Alice F. Tarantal, Barry J. Byrne

From the Center for Fetal Monkey Gene Transfer for Heart, Lung and Blood Diseases (A.F.T.), California National Primate Research Center; Departments of Pediatrics (C.A.P., C.S.M., B.D.T., T.J.C., M.A.L., D.E.C., I.Z., B.J.B.) and the Congenital Heart Center (B.J.B.), University of Florida, Gainesville; and Department of Pediatrics and Cell Biology and Human Anatomy (A.F.T.), University of California, Davis.

Correspondence to Barry J. Byrne, Department of Pediatrics, University of Florida, PO Box 100296, JHMHC, Gainesville, FL 32610-0296. E-mail bbyrne{at}ufl.edu

Heart disease is often the end result of inherited genetic defects, which may potentially be treatable using a gene-transfer approach. Recombinant adeno-associated virus (rAAV)-mediated gene delivery has emerged as a realistic method for the treatment of such disorders. Here, we demonstrate and compare the natural affinity of specific AAV serotype capsids for transduction of cardiac tissue. We compared the previously accepted optimal rAAV serotype for transduction of skeletal muscle, rAAV2/1, with rAAV2/8 and the newer rAAV2/9 vectors carrying the CMV-lacZ construct in their respective abilities to transcend vasculature and transduce myocardium following intravenous delivery of 1x10¹¹ vector genomes in neonatal mice. We found that both rAAV2/8 and rAAV2/9 are able to transduce myocardium at 20- and 200-fold (respectively) higher levels than rAAV2/1. Biodistribution analysis revealed that rAAV2/9 and rAAV2/8 demonstrate similar behavior in extracardiac tissue. Vector genome quantification showed an increase in genome copy numbers in cardiac tissue for several weeks following administration, which corresponds to expression data. In addition, we intravenously administered 1x10¹¹ vector genomes of rAAV2/9-CMV-lacZ into adult mice and achieved an expression biodistribution profile similar to that found following delivery to newborns. Although higher doses of virus will be necessary to approach those levels observed following neonatal injections, adult myocardium is also readily transduced by rAAV2/9. Finally, we have demonstrated physiological disease correction by AAV9 gene transfer in a mouse model of Pompe disease via ECG tracings and that intravenous delivery of the same vector preferentially transduces cardiac tissue in nonhuman primates.

Key Words: AAV9 • gene therapy • gene transfer • adeno-associated virus • cardiomyopathy

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