REDUCTION OF ATHEROSCLEROSIS IN APOE DEFICIENT MICE BY GENE THERAPY

载脂蛋白E(ApoE)是一种存在于极低密度脂蛋白(VLDL，IDL)中的299个氨基酸的蛋白质 以及在血浆代谢中起主要作用的高密度脂蛋白 脂蛋白。载脂蛋白E是低密度脂蛋白和残馀受体的主要配体 因此，对于正常清除来自 发行量。载脂蛋白E功能缺陷的患者可以 出现III型高脂蛋白血症和过早的动脉粥样硬化。 我们已经用标记替换了apoE缺陷小鼠的apoE基因 高胆固醇血症与自发性动脉粥样硬化 表达人载脂蛋白E基因的重组腺病毒(rapoE-adv)。 4月龄apoE缺陷雄性小鼠输注1×10~9pfu(n=15) 用FPLC对TC-644+49 mg/dl和高胆固醇极低密度脂蛋白/IDL进行预处理 导致血浆载脂蛋白E浓度的表达范围从3到 650 mg/dl和白天血脂和脂蛋白的正常化 4病毒注射后。载脂蛋白E表达与正常降血脂 在病毒注射后维持4周。分析 注射rapoE-Adv对载脂蛋白E缺陷小鼠主动脉病变的影响 显示平均病变面积显著减少(58+/-35×10 3亩平方米)与未经处理的小鼠(135+/-71×10亩平方米)和动物(135+/-71×10亩平方米)相比 注射rLuciferase-Adv(161+/-73×10~3亩~2)。 我们的研究证明成功地在载脂蛋白E中替代了人载脂蛋白E 使用重组腺病毒的缺陷小鼠。生理学的表现 1个月归一化血脂和载脂蛋白E浓度 脂蛋白，并导致平均主动脉病变显著减少 区域。载脂蛋白E缺陷小鼠的载脂蛋白E成功替代 人遗传性载脂蛋白基因治疗的可行性 不足之处。

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.