Development of novel tissue directed ultra sound therapeutic gene delivery system

描述(申请人提供)：低水平的高密度脂蛋白(高密度脂蛋白)胆固醇是冠心病的重要风险因素。高密度脂蛋白胆固醇水平可以预测接受他汀类药物治疗的患者的主要心血管事件。在低密度脂蛋白水平低于每分升70毫克的患者中也观察到了这种关系。研究表明，多核苷酸，如DNA和RNA，可以被输送到产生细胞变化的细胞中，从而产生治疗作用。为了成功地实现基因治疗，基因材料必须与有效的递送载体相结合，以提供局部治疗。编码表达全部或部分蛋白质的DNA可以直接、原位或通过转移到细胞中间接传递到有机体中，然后移植到有机体中。Sonogene公司正在研究将哺乳动物的非病毒转基因作为基因治疗的一种手段。本研究旨在建立一种靶向将DNA载体导入肝脏以增强载脂蛋白A-I表达的方法。这项拨款的申请是为了支持研究开发一种合适的非侵入性途径，以诱导肝脏中apoA-I基因的表达，以有利于改变胆固醇代谢。我们建议利用微球或微泡作为载体将裸质粒apoA-I DNA注射到血液中。肝脏中的毛细血管内皮细胞是有窗口的，并允许增强肝细胞对质粒的摄取。然后用超声波处理肝脏，破坏微球，导致肝脏内皮细胞一过性疏松，允许肝脏摄取和表达质粒DNA。与公众健康相关：高密度脂蛋白(高密度脂蛋白)胆固醇水平是冠心病的重要风险因素。低高密度脂蛋白胆固醇水平可以预测患者的主要心血管事件。Sonogene建议开发新的超声波技术来提高高密度脂蛋白的水平，作为一种心脏保护治疗策略。

DESCRIPTION (provided by applicant): Low levels of high-density lipoprotein (HDL) cholesterol is an important risk factor for coronary heart disease (CHD). HDL cholesterol levels are predictive of major cardiovascular events in patients treated with statins. This relationship was also observed among patients with LDL cholesterol levels below 70 mg per deciliter. Studies have demonstrated that polynucleotides, such as DNA and RNA, can be delivered to cells producing cellular changes that can be therapeutic. In order to successfully achieve gene therapy, it is essential that the genetic materials work in conjunction with an effective delivery vehicle to provide localized therapy. DNA coded to express a whole or partial protein can be delivered either directly to the organism, in situ, or indirectly by transfer to a cell that is then transplanted into the organism. SonoGene Corporation is researching the non-viral transfection of mammals as a means of gene therapy. It is proposed to develop a method for targeting the transfection of DNA plasmid to the liver to enhance apoA-I expression. The request for this grant is to support research in developing a suitable non-invasive route to induce apoA-I gene expression in the liver for the purpose of favorably altering cholesterol metabolism. We propose to inject naked plasmid apoA-I DNA into the blood utilizing microspheres or microbubbles as a delivery vehicle. The capillary endothelial cells in the liver are fenestrated and permit enhanced uptake of plasmids into liver cells. The liver is then treated with ultrasound waves that disrupt the microspheres and cause transient porosity of liver endothelial cells, allowing for the uptake and expression of plasmid DNA by the liver. PUBLIC HEALTH RELEVANCE: High-density lipoprotein (HDL) cholesterol level is an important risk factor for coronary heart disease. Low HDL cholesterol levels are predictive of major cardiovascular events in patients. SonoGene proposes to develop novel ultrasound technology to raise HDL cholesterol levels as a cardio-protective therapeutic strategy.