REDUCTION OF ATHEROSCLEROSIS IN APOE DEFICIENT MICE BY GENE THERAPY

载脂蛋白E（apoE）是存在于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HDL 脂蛋白ApoE是LDL和残余受体的主要配体 因此，对于残余颗粒的正常清除是必要的 流通。apoE功能缺陷的患者可以 发展为III型高脂蛋白血症和过早的动脉粥样硬化。 我们已经用标记的apoE基因替换了apoE缺陷小鼠的apoE基因， 高胆固醇血症和自发性动脉粥样硬化 表达人apoE基因的重组腺病毒（rapoE-AdV）。 在4月龄apoE缺陷型雄性小鼠中输注1 × 10 9 pfu（n=15） 治疗前TC-644+49 mg/dl和富胆固醇VLDL/IDL（FPLC） 导致血浆apoE浓度的表达范围为3 - 10 μ g/ml， 650 mg/dl和血浆脂质和脂蛋白的日间正常化 4病毒注射后。ApoE表达与正常血脂降低 在病毒注射后维持4周。分析 apoE缺陷小鼠注射rapoE-AdV后主动脉病变的 显示平均病变面积显著减小（58+/-35 X 10 3 μ m2）与未处理小鼠（135+/-71 x 10 μ m2）和动物相比 注射rLuciferase-AdV（161+/-73 × 103 μ m2）。 我们的研究证明了apoE中人apoE的成功替代 缺陷型小鼠使用重组腺病毒。生理表达 1个月标准化血浆脂质的apoE浓度， 脂蛋白，并导致平均主动脉病变显着减少 区在apoE缺陷小鼠中成功替代apoE证明了 人遗传性载脂蛋白基因治疗可行性 缺陷

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.