SOMATIC GENE THERAPY FOR CARDIOVASCULAR DISEASES

心血管疾病的体细胞基因治疗

• 批准号: 2519371
• 负责人: LOUIS C. SMITH
• 金额: $ 114.62万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-09-01 至 1998-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2519371
• 关键词: atherosclerosis; cardiovascular disorder; gene therapy

Cardiovascular disease is a major public health problem and has been the leading cause of death in the United States for decades. A significant fraction of the disease is the result of atherosclerosis and heart disease. The high fat diet consumed in the Western world is a direct cause of elevated LDL-cholesterol and triglyceride levels in blood which result in the formation of atherosclerotic plaques in the vasculature. Current treatment relies mainly on the reduction of plasma LDL- cholesterol by administering pharmaceuticals that either reduce cholesterol biosynthesis or accelerate cholesterol disposal and requires life-long medications that may have long-term side effects. Hyperlipidemias are polygenic disorders that strongly predispose individuals to the development of atherosclerosis. It is well established in animal studies that the pathologic phenotypes can be prevented or improved by enhanced expression of the LDL-receptor, apolipoprotein A1, cholesterol-7a-hydroxylase and lipoprotein lipase genes. With the advent in technologies for gene transfer into animals that result in their constitutive expression in vivo, the therapeutic genes for atherosclerosis can be introduced somatically into the proper organs for expression that may provide a long-term cure for the disease. As the natural organs for biosynthesis of these genes are the liver and the muscle, and technologies for somatic gene delivery into these organs are already mastered in various laboratories at Baylor College of Medicine, the current program project proposal will focus on the refinement of existing technologies as well as the development of novel vector systems for efficient delivery and enhanced expression of the plasma lipid modulating genes in the liver and the muscle. The initial experimental animal model system will be the Watanabe hereditary hyperlipidemic rabbits and other genetic animal models created by either transgenic introduction of atherosclerotic genes or inactivation of protective genes by targeted recombination in embryonic stem cells. Atherosclerotic animals induced by high fat diet will also be used to test the hypothesis that these plasma lipid-modulating genes are therapeutic for atherosclerosis caused by a wide spectrum of genetic factors. Phenotype correction of plasma lipid profiles and subsequent prevention of atherosclerogenic plaque formation in the vasculature of the genetic and dietary animal model systems will form the scientific basis for the future correction of atherosclerosis and coronary heart disease in man by somatic gene therapy.

心血管疾病是重大公共卫生问题，已成为人们关注的焦点 几十年来一直是美国的首要死因。 一个重要的 该疾病的一部分是动脉粥样硬化和心脏疾病的结果 疾病。 西方世界消费的高脂肪饮食是直接影响 血液中低密度脂蛋白胆固醇和甘油三酯水平升高的原因 导致血管系统中动脉粥样硬化斑块的形成。 目前的治疗主要依靠降低血浆LDL- 通过服用可降低胆固醇的药物 胆固醇生物合成或加速胆固醇处理并需要 可能有长期副作用的终生药物。 高脂血症是一种多基因疾病，极易诱发 个人发展为动脉粥样硬化。 很好 动物研究证实病理表型可以是 通过增强 LDL 受体的表达来预防或改善， 载脂蛋白 A1、胆固醇 7a 羟化酶和脂蛋白脂肪酶 基因。 随着将基因转移到动物体内的技术的出现 导致它们在体内的组成型表达，治疗 动脉粥样硬化的基因可以通过体细胞导入到适当的 表达的器官可能会为该疾病提供长期治愈。 由于生物合成这些基因的天然器官是肝脏和 肌肉以及将体细胞基因传递到这些器官的技术 已经在贝勒学院的各个实验室掌握 医学方面，目前的计划项目提案将重点关注 改进现有技术以及开发新颖的技术 用于高效递送和增强表达的载体系统 肝脏和肌肉中的血浆脂质调节基因。 最初的 实验动物模型系统将由渡边世袭 高脂血症兔子和其他遗传动物模型 转基因引入动脉粥样硬化基因或灭活 通过胚胎干细胞中的靶向重组来保护基因。 高脂肪饮食诱发的动脉粥样硬化动物也将被用来 检验这些血浆脂质调节基因的假设 治疗由多种遗传因素引起的动脉粥样硬化 因素。 血浆脂质谱的表型校正和后续 预防血管系统中动脉粥样硬化斑块的形成 遗传和饮食动物模型系统将形成科学 为今后纠正动脉粥样硬化和冠心病奠定基础 通过体细胞基因疗法治疗人类疾病。

项目成果

The cotton rat in biomedical research.

生物医学研究中的棉鼠。

• 发表时间: 1997
• 期刊: Laboratory animal science
• 作者: Faith,RE;Montgomery,CA;Durfee,WJ;Aguilar-Cordova,E;Wyde,PR
• 通讯作者: Wyde,PR

Gene therapy in heart disease.

心脏病的基因治疗。

• DOI: 10.1007/978-1-4615-1957-7_8
• 发表时间: 1995
• 期刊: Advances in experimental medicine and biology
• 作者: Smith,LC;Eisensmith,RC;Woo,SL
• 通讯作者: Woo,SL

Potential salmon sperm origin of the E3 region insert of the adenovirus 5 dl309 mutant.

腺病毒 5 dl309 突变体 E3 区插入物的潜在鲑鱼精子起源。

• 发表时间: 1996
• 期刊: Cancer gene therapy.
• 作者: Gingras,MC;Arevalo,P;Aguilar-Cordova,E
• 通讯作者: Aguilar-Cordova,E

Local overexpression of thrombomodulin for in vivo prevention of arterial thrombosis in a rabbit model.

血栓调节蛋白的局部过度表达可在兔模型中体内预防动脉血栓形成。

• DOI: 10.1161/01.res.84.1.84
• 发表时间: 1999
• 期刊: Circulation research
• 影响因子: 20.1
• 作者: Waugh,JM;Yuksel,E;Li,J;Kuo,MD;Kattash,M;Saxena,R;Geske,R;Thung,SN;Shenaq,SM;Woo,SL
• 通讯作者: Woo,SL

Thrombomodulin overexpression to limit neointima formation.

血栓调节蛋白过度表达以限制新内膜形成。

• DOI: 10.1161/01.cir.102.3.332
• 发表时间: 2000
• 期刊: Circulation
• 影响因子: 37.8
• 作者: Waugh,JM;Li-Hawkins,J;Yuksel,E;Kuo,MD;Cifra,PN;Hilfiker,PR;Geske,R;Chawla,M;Thomas,J;Shenaq,SM;Dake,MD;Woo,SL
• 通讯作者: Woo,SL