Recombinant Adeno-Associated Virus-Mediated Gene Therapy for Treatment of Familial Hypercholesterolemia in Rabbits
Recombinant Adeno-Associated Virus-Mediated Gene Therapy for Treatment of Familial Hypercholesterolemia in Rabbits
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Date
2013
Authors
Atlas, Daniel
Buckshaw, Elizabeth
Hanna, David
Lannon, Jennifer
Mahmud, Alia
Mirvis, Mary
Pham, Anna
Ramnarain, Nadira
Randazzo, Paul
Safferman, Michelle
Advisor
Bossis, Ioannis
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DRUM DOI
Abstract
Familial hypercholesterolemia (FH) is a genetic disorder characterized by
abnormally high concentrations of low-density lipoprotein-cholesterol (LDLcholesterol)
in the blood that can contribute to heart disease. FH can result from a
defect in the gene for the LDL receptor (LDL-R). FH patients lacking functional
LDL-R may benefit from viral-mediated transfer of a functional copy of the open
reading frame (ORF) of the LDL-R. Since a recombinant adeno-associated virus
(rAAV) is not immunogenic and can be mass-produced, it shows promise for
gene therapy applications. AAV6 and AAV8 have been shown to specifically
transduce hepatocytes in several species, which normally remove the majority of
LDL-cholesterol from the blood via LDL-R-mediated endocytosis. Because of the
potential of rAAV to treat FH by delivery of a correct LDL-R ORF to hepatocytes, the liver specificity of these two AAV serotypes was evaluated.
Additionally, rabbits were chosen as the animal model for this study because a
specific strain of rabbits, Watanabe heritable hyperlipidemic (WHHL), adequately
mimics the pathology of FH in humans. Exposure of rabbit liver to rAAV with the
marker LacZ and subsequent inspection of liver tissue showed that AAV8 transduced rabbit liver more efficiently than AAV6. To assess the feasibility of
producing a rAAV capable of transferring the LDL-R ORF to rabbit hepatocytes in vivo, rAAV8-LDL-R was mass-produced by a baculovirus system in suspension grown insect cells.