Recombinant Adeno-Associated Virus-Mediated Gene Therapy for Treatment of Familial Hypercholesterolemia in Rabbits

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dc.contributor.advisorBossis, Ioannis
dc.contributor.authorAtlas, Daniel
dc.contributor.authorBuckshaw, Elizabeth
dc.contributor.authorHanna, David
dc.contributor.authorLannon, Jennifer
dc.contributor.authorMahmud, Alia
dc.contributor.authorMirvis, Mary
dc.contributor.authorPham, Anna
dc.contributor.authorRamnarain, Nadira
dc.contributor.authorRandazzo, Paul
dc.contributor.authorSafferman, Michelle
dc.contributor.authorZuckerberg, Jeremy
dc.date.accessioned2013-05-01T18:59:28Z
dc.date.available2013-05-01T18:59:28Z
dc.date.issued2013
dc.description.abstractFamilial 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.en_US
dc.identifier.urihttp://hdl.handle.net/1903/13880
dc.language.isoen_USen_US
dc.relation.isAvailableAtDigital Repository at the University of Maryland
dc.relation.isAvailableAtGemstone Program, University of Maryland (College Park, Md)
dc.subjectGemstone Team Gene Therapyen_US
dc.subjectgene therapyen_US
dc.subjectFamilial hypercholesterolemiaen_US
dc.subjectrabbitsen_US
dc.titleRecombinant Adeno-Associated Virus-Mediated Gene Therapy for Treatment of Familial Hypercholesterolemia in Rabbitsen_US
dc.typeThesisen_US

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