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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:1852.)
© 2006 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Complete Prevention of Atherosclerosis in ApoE-Deficient Mice by Hepatic Human ApoE Gene Transfer With Adeno-Associated Virus Serotypes 7 and 8

Ken Kitajima; Dawn H.L. Marchadier; Gwen C. Miller; Guang-ping Gao; James M. Wilson; Daniel J. Rader

From Institution for Translational Medicine and Therapeutics (K.K., G.C.M., D.H.M., D.J.R.) and Gene Therapy Program, Division of Medical Genetics (G.G., J.M.W.), Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pa.

Correspondence to Daniel J. Rader, Associate Professor of Medicine, University of Pennsylvania Medical Center, 654 BRBII/III Labs, 421 Curie Blvd, Philadelphia, PA 19104-6160. E-mail rader{at}mail.med.upenn.edu

Objective— Using intravenous injection of adeno-associated viral (AAV) vectors based on novel serotypes 7 and 8, we examined whether liver-specific expression of human apolipoprotein E (apoE) in apoE-deficient mice would completely prevent atherosclerosis after 1 year of sustained expression.

Methods and Results— Chow-fed apoE^–/– mice were injected via the tail vein with vectors based on AAV2 or novel serotypes AAV7 and AAV8 encoding human apoE3 driven by a liver-specific promoter. In contrast to the first-generation AAV2 vector, apoE levels of mice injected with chimeric AAV2/7 and AAV2/8 vectors reached 2-fold greater than normal human plasma levels by week 4 and maintained therapeutic levels up to 1 year. Cholesterol levels of AAV2/7-apoE and AAV2/8-apoE–treated mice were reduced to normal murine wild-type levels and were maintained for 1 year. At termination after 1 year, extensive atherosclerosis was present in the thoracic aortas and aortic roots of control AAV2/8-lacZ and AAV2-apoE–injected mice, but was completely prevented in both the AAV2/7 and AAV2/8-apoE–treated mice.

Conclusion— We demonstrate that intravenous administration of AAV2/7- and AAV2/8-apoE vectors effectively mediated robust and sustained hepatic-specific expression of apoE and completely prevented atherosclerosis at 1 year.

Intravenous administration of AAV2/7- and AAV2/8-apoE vectors effectively mediated robust and sustained hepatic-specific expression of apoE in apoE-deficient mice, resulting in complete prevention of atherosclerosis at 1 year.

Key Words: adeno-associated virus • apolipoprotein E • atherosclerosis • gene therapy

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