Complete prevention of atherosclerosis in apoE-deficient mice by hepatic human apoE gene transfer with adeno-associated virus serotypes 7 and 8.
OBJECTIVE
Using intravenous injection of adeno-associated viral (AAV) vectors based on novel serotypes 7 and 8, we examined whether liver-specific expression of human apolipoprotein E (apoE) in apoE-deficient mice would completely prevent atherosclerosis after 1 year of sustained expression.


RESULTS
Chow-fed apoE-/- mice were injected via the tail vein with vectors based on AAV2 or novel serotypes AAV7 and AAV8 encoding human apoE3 driven by a liver-specific promoter. In contrast to the first-generation AAV2 vector, apoE levels of mice injected with chimeric AAV2/7 and AAV2/8 vectors reached approximately 2-fold greater than normal human plasma levels by week 4 and maintained therapeutic levels up to 1 year. Cholesterol levels of AAV2/7-apoE and AAV2/8-apoE-treated mice were reduced to normal murine wild-type levels and were maintained for 1 year. At termination after 1 year, extensive atherosclerosis was present in the thoracic aortas and aortic roots of control AAV2/8-lacZ and AAV2-apoE-injected mice, but was completely prevented in both the AAV2/7 and AAV2/8-apoE-treated mice.


CONCLUSIONS
We demonstrate that intravenous administration of AAV2/7- and AAV2/8-apoE vectors effectively mediated robust and sustained hepatic-specific expression of apoE and completely prevented atherosclerosis at 1 year.
Kitajima
Ken
K
Institution for Translational Medicine and Therapeutics, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
Marchadier
Dawn H L
DH
Miller
Gwen C
GC
Gao
Guang-ping
GP
Wilson
James M
JM
Rader
Daniel J
DJ
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D050197:Atherosclerosis / Q000517:prevention & control*; D000229:Dependovirus / Q000145:classification / Q000235:genetics*; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000008:administration & dosage; D006801:Humans; D007275:Injections, Intravenous; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D012703:Serotyping; D013997:Time Factors
D001057:Apolipoproteins E