title: Safe 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 transfer.
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.
authors.affiliation: Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Cimmino
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.forename: Walter S
authors.initials: WS
authors.lastname: Speidl
authors.forename: Chiara
authors.initials: C
authors.lastname: Giannarelli
authors.forename: Borja
authors.initials: B
authors.lastname: Ibanez
authors.forename: Valentin
authors.initials: V
authors.lastname: Fuster
authors.forename: Roger
authors.initials: R
authors.lastname: Hajjar
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Walsh
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Badimon
mesh_terms: D000818:Animals; D016632:Apolipoprotein A-I / Q000097:blood / Q000172:deficiency / Q000235:genetics*; D015153:Blotting, Western; D002460:Cell Line; D003402:Creatine Kinase / Q000097:blood; D000229:Dependovirus / Q000145:classification / Q000235:genetics*; D015870:Gene Expression; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000633:toxicity; D006801:Humans; D007273:Injections, Intramuscular; D008075:Lipoproteins, HDL / Q000097:blood / Q000172:deficiency / Q000235:genetics*; D008077:Lipoproteins, LDL / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D010084:Oxidation-Reduction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
chemical_list: D016632:Apolipoprotein A-I; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D003402:Creatine Kinase