AAV MEDIATED APO A1 GENE THERAPY FOR ATHEROSCLEROSIS

AAV 介导的 APO A1 基因治疗动脉粥样硬化

• 批准号: 6189142
• 负责人: Prediman Krishan Shah
• 金额: $ 34.71万
• 依托单位: CITY OF HOPE NATIONAL MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-01 至 2000-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6189142
• 关键词: adeno associated virus group; antiatherogenic agent; apolipoprotein E; apolipoproteins; artery stenosis; atherosclerotic plaque; gene therapy; genetically modified animals; high density lipoproteins; human genetic material tag; laboratory mouse; nonhuman therapy evaluation; swine; vascular endothelium

Animal studies have provided compelling evidence in favor of direct anti- atherogenic effects pf JD;-C and apolipoprotein A I (apo A-I). While low HDL-C levels are often associated with an increased risk of coronary artery diseases, human carriers of the Milano mutation in the apo A-I gene are remarkable in that despite extremely low levels of HDL-C, they enjoy freedom from vascular disease and have an ancestral history of longevity. These observations have suggested that the apo A-I/Milano, compared to the wild type apo A-I, apo A-I/wt. While the results of intravenous administration of these rHDL particles have provided evidence of their anti- atherogenic efficacy, the need for repeated intravenous administration remains a practical limitation. Therefore, somatic gene therapy to induce in vivo production of apo A-I offers an alternative approach for utilizing the anti-atherogenic effects of apo A-I. Recently, long-term in vivo expression of transgenes delivered by recombinant adeno-associated virus (rAAV) vectors have been demonstrated. Therefore, in this project we will explore the feasibility and biologic efficacy of gene therapy utilizing rAAV vectors containing the apo A-I/wt and apo A-I/Milano genes in preventing atherosclerosis and pot-injury intimal hyperplasia in the apo E-deficient mouse model. Studies using mouse model of arterial injury will be extended to a large animal model to examine the effects of local gene delivery on the coronary arterial luminal narrowing following balloon overstretch and stent over-inflation injury in swine. The application of gene therapy with apo A- I/wt/apo A-I/Milano gene in the swine vascular injury model may provide the type of preclinical studies needed to demonstrate the feasibility of apo A-I gene therapy in humans. The specific aims are: 1) Analysis of transgene expression in mice following in vivo administration of rAAV vectors encoding apo A-I/wt and apo A-I/Milano genes, 2) Effect of rAAV- mediated transfer of apo A-I/wt and apo A-I/Milano genes on arterial response to carotid injury in apo E-deficient mice, 3) Assessment of feasibility and efficacy of gene transfer using macrophages transduced with rAAV vectors encoding human apo A-I/wt and apo A-I/Milano, and 4) Evaluation of the effects of local rAAV mediated transfer of human apo A- I/wt and apo A-I/Milano genes on coronary arterial luminal narrowing response to balloon-overstretch and stent-overinflation injury in swine.

动物研究提供了令人信服的证据，支持直接的抗动脉粥样硬化作用PF JD; -c和载脂蛋白A I（APO A-I）。尽管低HDL-C水平通常与冠状动脉疾病的风险增加有关，但Apo A-I基因中米拉诺突变的人类携带者非常显着，因为尽管HDL-C水平极低，但它们享有血管疾病的自由，并且具有寿命的寿命。这些观察结果表明，与野生型Apo A-I，Apo A-I/WT相比，Apo A-I/Milano。尽管这些RHDL颗粒的静脉内给药结果提供了其抗动脉粥样硬化疗效的证据，但需要重复静脉内给药的需求仍然是一个实际的限制。因此，诱导体内产生Apo A-I的体细胞基因疗法为利用APO A-I的抗毒药作用提供了另一种方法。最近，已经证明了由重组腺相关病毒（RAAV）载体传递的转基因的长期体内表达。因此，在这个项目中，我们将利用含有APO A-I/WT和APO A-I/Milano基因的RAAV载体的基因治疗的可行性和生物学功效，以防止动脉粥样硬化和POT-POT-INJURY INIMALIMAL增生在APO E-E-DeCeentecient小鼠模型中。使用小鼠模型的动脉损伤模型的研究将扩展到大型动物模型，以检查局部基因递送对猪的气球过度伸展和支架过度通气损伤后，局部基因递送对冠状动脉腔狭窄的影响。在猪血管损伤模型中使用APO A-I/WT/APO A-I/Milano基因的基因治疗可能提供了证明人类APO A-I基因治疗可行性所需的临床前研究的类型。 The specific aims are: 1) Analysis of transgene expression in mice following in vivo administration of rAAV vectors encoding apo A-I/wt and apo A-I/Milano genes, 2) Effect of rAAV- mediated transfer of apo A-I/wt and apo A-I/Milano genes on arterial response to carotid injury in apo E-deficient mice, 3) Assessment of feasibility and efficacy of使用编码人apo a-i/wt和apo a-i/milano的raav载体转导的巨噬细胞的基因转移，以及4）评估局部RAAV介导的人apo a-i/wt和apo a-i/wt和apo a-i/米兰诺基因对冠状动脉动脉衰减对球球nimallow numberoon-offertict and senterfortict and senterfort的影响。