Adeno-associated virus serotypes 7 and 8 outperform serotype 9 in expressing atheroprotective human apoE3 from mouse skeletal muscle

Vanessa C Evans, Ian R Graham, Takis Athanasopoulos, Debbie J Galley, Chris Jackson, JP Simons, G Dickson, JS Owen

Research output: Contribution to journalArticle (Academic Journal)peer-review

5 Citations (Scopus)

Abstract

Intramuscular injection of adeno-associated viral (AAV) vectors is potentially a safe, minimally invasive procedure for the long-term gene expression of circulating antiatherogenic proteins. Here, we compare secretion and atheroprotective effects of human apoE3 after injection of 3 pseudotyped AAV vectors (AAV2/7, AAV2/8, or AAV2/9), driven by the CMV enhancer/chicken beta-actin (CAG) promoter, into skeletal muscle of hyperlipidemic apolipoprotein E-deficient (apoE(-/-)) mice. Vector viabilities were verified by transducing cultured C2C12 mouse myotubes and assessing secretion of human apoE3 protein. Both hind limb tibialis anterior muscles of female C57BL/6 apoE(-/-) mice, 2 months old and fed a high-fat diet, were each injected with 1 x 10(10) vector genomes of AAV vector. Identical noninjected mice served as controls; and blood was collected at weeks 0, 1, 2, 4, and 13. At termination (13 weeks), the brachiocephalic artery was excised; and after staining sections, plaque morphometry and fractional lipid content were quantified by computerized image analysis. Intramuscular injection of AAV2/7 and AAV2/8 vectors produced up to 2 mug human apoE3 per milliliter plasma, just below the threshold to reverse dyslipoproteinemia. AAV2/9 was notably less effective, mice having a 3-fold lower level of plasma apoE3 at 13 weeks and a 50% greater burden of atherosclerotic plaque lipid in their brachiocephalic arteries. We conclude that although vector refinement is needed to exploit fully apoE3 atheroprotective functions, AAV2/7 and AAV2/8 are promising gene transfer vectors for muscle-based expression of antiatherogenic circulating proteins.
Translated title of the contributionAdeno-associated virus serotypes 7 and 8 outperform serotype 9 in expressing atheroprotective human apoE3 from mouse skeletal muscle
Original languageEnglish
Pages (from-to)491-498
Number of pages8
JournalMetabolism
Volume60
Issue number4
DOIs
Publication statusPublished - Apr 2011

Bibliographical note

Publisher: Metabolism

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