Helper-dependent adenoviral vector-mediated long-term expression of human apolipoprotein A-I reduces atherosclerosis in apo E-deficient mice.
Apolipoprotein A-I (APOA-I) is the major protein component of high-density lipoproteins (HDL). It has been shown that over-expression of human APOA-I increases HDL cholesterol and decreases atherosclerosis. We constructed a helper-dependent adenoviral (HD-Ad) vector that contains the entire human APOA-I gene (hgAI). Intravenous delivery of 1x10(13) viral particles/kg of this vector was followed by high levels of human APOA-I expression (up to 200 mg/dl) in the absence of detectable hepatic toxicity. We treated apo E-deficient mice with the hgAI vector and fed them either with a high-fat diet or with regular chow. As a control, two groups of mice were treated with PBS. The apo E-deficient mice treated with the hgAI vector showed supraphysiological levels of expression of human APOA-I at week 4 and high levels of HDL cholesterol compared to the control groups. Analysis of aortic atherosclerotic lesions 20 weeks after treatment, showed a significant reduction of lesion size in the treated mice with both diets. In conclusion, liver-directed gene transfer of human APOA-I using a HD-Ad vector resulted in a reduction of the development of atherosclerosis with the absence of significant toxicity.
Pastore
Lucio
L
Department of Molecular and Human Genetics, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA. pastore@dbbm.unina.it
Belalcazar
L Maria
LM
Oka
Kazuhiro
K
Cela
Racel
R
Lee
Brendan
B
Chan
Lawrence
L
Beaudet
Arthur L
AL
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000473:pathology; D016632:Apolipoprotein A-I / Q000235:genetics / Q000378:metabolism*; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D001161:Arteriosclerosis / Q000097:blood / Q000473:pathology* / Q000517:prevention & control; D008076:Cholesterol, HDL / Q000097:blood; D015870:Gene Expression; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics*; D006378:Helper Viruses / Q000235:genetics; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013997:Time Factors
D016632:Apolipoprotein A-I; D001057:Apolipoproteins E; D008076:Cholesterol, HDL