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Publication Detail
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
  • Publication Type:
    Journal article
  • Publication Sub Type:
    Article
  • Authors:
    Osman E, Evans V, Graham IR, Athanasopoulos T, McIntosh J, Nathwani AC, Simons JP, Dickson GO, J S
  • Publication date:
    2008
  • Pagination:
    121, 126
  • Journal:
    Atherosclerosis
  • Volume:
    204
  • Issue:
    1
  • Print ISSN:
    0021-9150
  • Keywords:
    Adeno-associated virus serotype-8; Atherosclerosis; Cholesterol; Gene therapy; Lipoproteins; Liver-specific promoter; Viral gene transfer
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 (LP1), 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 1x10(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 (up to 17 microg/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.
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