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Preliminary evaluation of a self-complementary AAV2/8 vector for hepatic gene transfer of human apoE3 to inhibit atherosclerotic lesion development in apoE-deficient mice

Osman, E; Evans, V; Graham, IR; Athanasopoulos, T; McIntosh, J; Nathwani, AC; Simons, JP; ... Owen, JS; + view all (2009) Preliminary evaluation of a self-complementary AAV2/8 vector for hepatic gene transfer of human apoE3 to inhibit atherosclerotic lesion development in apoE-deficient mice. ATHEROSCLEROSIS , 204 (1) 121 - 126. 10.1016/j.atherosclerosis.2008.08.043.

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Abstract

Hepatic gene transfer of atheroprotective human apoE by recombinant viral vectors can reverse hypercholesterolaemia and inhibit atherogenesis in apoE-deficient (apoE(-/-)) mice. Here, in preliminary studies we assess the effectiveness of a recently developed self-complementary adeno-associated Virus (scAAV) serotype 8 vector, driven by a hepatocyte-specific promoter (LP I), for liver-directed gene delivery of human apoE3. Vector viability was validated by transducing cultured HepG2 cells and measuring secretion of apoE3 protein. Male and female apoE(-/-) mice, 6-month old and fed on normal chow, were intravenously injected with 1 x 10(11) vg (vector genomes) of scAAV2/8.LP1.apoE3; age-matched Untreated mice served as controls. In male mice, plasma apoE3 levels were Sufficiently high (Lip to 17 mu g/ml) to normalize plasma total cholesterol and ameliorate their proatherogenic lipoprotein profile, by reducing VLDL/LDL and increasing HDL 5-fold. At termination (12 weeks) development of aortic atherosclerosis was significantly retarded by 58%(aortic lesion area 8.2 +/- 1.4% vs. 19.3 +/- 2.4% in control males: P<0.001). Qualitatively similar anti-atherogenic effects were noted when female mice were treated, but the benefits were less marked and aortic lesions, for example, were reduced by only 33% (15.7 +/- 3.7% vs. 23.6 +/- 6.9%). Although group numbers were small (n = 4/5), this gender-specific difference reflected two to three times less apoE3 in plasma of female mice at weeks 3 and 6. implying that gene transfer to female liver using scAAV vectors may require additional optimization, despite their established Superior potency to conventional single-stranded (ssAAV) vectors. (C) 2008 Elsevier Ireland Ltd. All rights reserved.

Type: Article
Title: Preliminary evaluation of a self-complementary AAV2/8 vector for hepatic gene transfer of human apoE3 to inhibit atherosclerotic lesion development in apoE-deficient mice
DOI: 10.1016/j.atherosclerosis.2008.08.043
Keywords: Adeno-associated virus serotype-8, Atherosclerosis, Cholesterol, Gene therapy, Lipoproteins, Liver-specific promoter, Viral gene transfer, ADENOASSOCIATED VIRUS VECTORS, HUMAN APOLIPOPROTEIN-E, EFFICIENT TRANSDUCTION, VIRAL VECTORS, IN-VIVO, EXPRESSION, LIVER, MURINE, SEROTYPE-8, REGRESSION
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Haematology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Inflammation
URI: http://discovery.ucl.ac.uk/id/eprint/87324
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