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J Thorac Cardiovasc Surg 2003;126:671-679
© 2003 The American Association for Thoracic Surgery

Cardiopulmonary support and physiology

Direct comparison of efficiency and stability of gene transfer into the mammalian heart using adeno-associated virus versus adenovirus vectors

^a Division of Cardiothoracic Surgery, University of California at San Diego, San Diego, Calif, USA
^b Salk Institute for Biological Studies, La Jolla, Calif, USA
^c Department of Pathology, Veterans Administration Medical Center, La Jolla, Calif, USA

Received for publication March 5, 2002; revisions received August 19, 2002; revisions received October 11, 2002; accepted for publication December 4, 2002.

^* Address for reprints: Patricia A. Thistlethwaite, MD, PhD, University of California at San Diego, Division of Cardiothoracic Surgery, 200 West Arbor Dr, San Diego, CA 92103-8892, USA
pthistlethwaite{at}ucsd.edu

OBJECTIVE: Recent gene therapy strategies have relied on the use of adenovirus or plasmid as vehicles for gene delivery to the heart. These approaches have been limited by low transduction frequencies and transient transgene expression. We sought to determine whether adeno-associated virus produces more stable, higher efficiency gene expression in the rodent heart than did previous conventional methods.

METHODS: Two recombinant viral constructs were made: an adeno-associated virus containing the lacZ gene under the control of the cytomegalovirus promoter (AAV-lacZ) and an adenovirus expressing lacZ under the control of the same promoter (Adeno-lacZ). Twenty rats were injected (into the ventricular apex) with 1 x 10^7-8 genomic particles of each virus. Animals were put to death at serial time points and transgene expression quantitated by ß-galactosidase activity, myocardial staining, and Western blot protein analysis.

RESULTS: Three months after adeno-associated virus gene transfer, animals demonstrated stable ß-galactosidase expression in 60% of cardiomyocytes without evidence of myocardial inflammation/necrosis. The distribution and degree of protein expression and number of positive cells at 3 months were equivalent to transgene expression at 4 weeks. Adeno-associated virus was not detected in organs other than the heart. In contrast, Adeno-lacZ animals displayed transient ß-galactosidase activity in 60% of cardiomyocytes, which was undetectable 4 weeks after gene transfer. Adenovirus-treated animals manifest significant myocardial inflammation and had transgene expression in other organs.

CONCLUSION: Direct intramyocardial injection of an adeno-associated virus vector programs stable, long-term, cardiac-specific transgene expression in the rodent heart for up to 3 months. Our results suggest adeno-associated virus has significant advantages for long-term transgene expression in the heart compared to adenovirus vectors.

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