REDUCTION OF ATHEROSCLEROSIS IN APOE DEFICIENT MICE BY GENE THERAPY

通过基因治疗减少 APOE 缺陷小鼠的动脉粥样硬化

• 批准号: 5203523
• 负责人: S SANTAMARINA-FOJO
• 金额: --
• 依托单位: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/5203523
• 关键词: Adenoviridae; apolipoproteins; atherosclerosis; blood lipoprotein metabolism; disease /disorder model; familial hyperlipoproteinemia type III; gene expression; gene therapy; genetically modified animals; human genetic material tag; hypercholesterolemia; laboratory mouse; nonhuman therapy evaluation; transfection /expression vector

Apolipoprotein E (apoE) is a 299 amino acid protein present in VLDL, IDL and HDL that plays a major role in the metabolism of plasma lipoproteins. ApoE is a major ligand for the LDL and remnant receptors and thus, necessary for the normal clearance of remnant particles from the circulation. Patients with a functional deficiency of apoE can develop Type III hyperlipoproteinemia and premature atherosclerosis. We have replaced the apoE gene in apoE deficient mice with marked hypercholesterolemia and spontaneous atherosclerosis by using recombinant adenovirus expressing the human apoE gene (rapoE-AdV). Infusion of 1 X 10 9 pfu in 4 month old apoE deficient male mice (n=15) with pre-treatment TC-644+49 mg/dl and cholesterol-rich VLDL/IDL by FPLC resulted in expression of plasma apoE concentrations ranging from 3 to 650 mg/dl and normalization of the plasma lipids and lipoproteins by day 4 post-virus injection. ApoE expression and normal reduced plasma lipids were maintained for a period of 4 weeks after virus injection. Analysis of aortic lesions in apoE deficient mice injected with rapoE-AdV demonstrated a marked reduction in the mean lesion area (58+/-35 X 10 3 mu m2)compared to untreated mice (135+/-71 x 10 mu m2) and animals injected with rLuciferase-AdV(161+/-73 X 10 3mu m2). Our studies demonstrate successful replacement of human apoE in apoE deficient mice using recombinant adenovirus. Expression of physiologic concentrations of apoE for 1 month normalized plasma lipids and lipoproteins and resulted in marked reduction in mean aortic lesion area. Successful replacement of apoE in apoE deficient mice demonstrates the feasibility of gene therapy for human genetic apolipoprotein deficiencies.

载脂蛋白E （apoE）是一种299个氨基酸的蛋白质，存在于VLDL和IDL中