Original ArticleSafe and Sustained Overexpression of Functional Apolipoprotein A-I/High-density Lipoprotein in Apolipoprotein A-I–null Mice by Muscular Adeno-associated Viral Serotype 8 Vector Gene TransferCimmino, Giovanni MD*; Chen, Wei MD†; Speidl, Walter S MD*; Giannarelli, Chiara MD, PhD*; Ibanez, Borja MD*; Fuster, Valentin MD, PhD‡; Hajjar, Roger MD§; Walsh, Christopher E MD, PhD†; Badimon, Juan J PhD*Author Information From the *Atherothrombosis Research Unit; †Division of Hematology and Medical Oncology; ‡Cardiovascular Institute; and §Cardiovascular Research Center, Mount Sinai School of Medicine, New York, NY. W. S. Speidl is now with the Division of Internal Medicine, University of Vienna, Vienna, Austria. B. Ibanez is now with the Cardiology Department, Fundación Jiménez Díaz-Capio, Madrid, Spain. Received for publication May 13, 2009; accepted July 8, 2009. B. Ibanez was funded by a fellowship from the Working Group on Ischemic Heart Disease of the Spanish Society of Cardiology. C. Giannarelli was granted by the Italian Society of Hypertension. The authors report no conflicts of interest. Reprints: Prof Juan J. Badimon, PhD, Atherothrombosis Research Unit, Mount Sinai School of Medicine, New York, NY 10029 (e-mail: email@example.com). Journal of Cardiovascular Pharmacology: November 2009 - Volume 54 - Issue 5 - p 405-411 doi: 10.1097/FJC.0b013e3181bad264 Buy Metrics Abstract High levels of high-density lipoprotein (HDL) have protective effects against atherosclerosis and cardiovascular diseases. The postulated mechanism of action for these benefits is an enhanced reverse cholesterol transport. Apolipoprotein A-I (ApoA-I) is the major protein of HDL. The clinical benefits of raising ApoA-I/HDL have been clearly established by clinical and epidemiological studies. Despite these observations, there are not very effective pharmacological means for raising HDL. ApoA-I gene delivery by viral vectors seems a promising strategy to raise ApoA-I/HDL levels. Sustained gene expression in animals and humans has been attained using adeno-associated viral (AAV) vectors. The aim of the present study was to determine the efficiency, safety, and biological activity of human ApoA-I intramuscularly delivered using an AAV vector in mice. AAV serotype 8 vectors encoding for human ApoA-I transgene were administered intraportally and intramuscularly in ApoA-I-deficient animals. ApoA-I levels were measured every 2 weeks post administration. The effectiveness of the generated HDL was tested in vitro in cholesterol-loaded macrophages. The administration of the vectors resulted in a significant and sustained increase in ApoA-I and HDL plasma levels for up to 16 weeks at similar extent by both routes of administration. Activity of the generated HDL in removal of cholesterol from cholesterol-loaded macrophages was similar in both groups. Our data suggest that intramuscular AAV8-mediated gene transfer of human ApoA-I results in a significant and maintained increase in ApoA-I and functional HDL. © 2009 Lippincott Williams & Wilkins, Inc.