SOMATIC GENE THERAPY FOR CARDIOVASCULAR DISEASES

心血管疾病是一个主要的公共卫生问题， 几十年来一直是美国的头号死因 显著 这种疾病的一部分是动脉粥样硬化和心脏病的结果。 疾病 西方世界的高脂肪饮食是一种直接的 导致血液中LDL-胆固醇和甘油三酯水平升高， 导致血管系统中动脉粥样硬化斑块的形成。 目前的治疗主要依赖于降低血浆LDL- 通过服用药物， 胆固醇生物合成或加速胆固醇处置， 可能有长期副作用的终身药物。 高血压是多基因疾病， 个体对动脉粥样硬化的发展。 公 在动物研究中建立了病理表型， 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 导致它们在体内组成型表达， 动脉粥样硬化的基因可以通过体细胞的方式导入到 表达器官，可能为疾病提供长期治疗。 由于这些基因生物合成的天然器官是肝脏， 以及将体细胞基因导入这些器官的技术 已经在贝勒大学的多个实验室中掌握， 医学，目前的计划项目建议将集中在 现有技术的改进以及新技术的开发 用于有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。 初始 实验动物模型系统将渡边遗传 高脂血症兔和其他遗传动物模型， 动脉粥样硬化基因的转基因导入或失活 保护基因在胚胎干细胞中的靶向重组。 还将使用由高脂肪饮食诱导的动脉粥样硬化动物， 检验这些血浆脂质调节基因是 治疗由广泛的遗传因素引起的动脉粥样硬化 因素 血脂谱的表型校正和随后的 预防动脉粥样硬化斑块在血管系统中的形成 遗传和饮食动物模型系统将形成科学的 动脉粥样硬化和冠心病的未来校正的基础 通过体细胞基因疗法治疗人类疾病。

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.