Development of novel tissue directed ultra sound therapeutic gene delivery system

新型组织定向超声治疗基因递送系统的开发

基本信息

批准号：
8018829
负责人：
Eric Coles
金额：
$ 35.7万
依托单位：
SONOGENE, LLC
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8018829
关键词：
Animals Apolipoprotein A-I Blood Blood Volume Capillary Endothelial Cell Cardiovascular system Cell Nucleus Cells Cholesterol Homeostasis Clinical Trials Code Coronary heart disease DNA DNA delivery Data Development Dose Ear Endothelial Cells Event Gene Expression Gene Transfer General Population Genes Genetic Materials Goals Grant Hepatocyte High Density Lipoprotein Cholesterol High Density Lipoproteins Human In Situ Injection of therapeutic agent LDL Cholesterol Lipoproteins Legal patent Length Liver Local Therapy Mammals Messenger RNA Methodology Methods Microbubbles Microspheres Modeling Mus Nicotinic Acids Organism Oryctolagus cuniculus Other Genetics Patients Peripheral Pharmaceutical Preparations Phase Plasma Plasmids Polynucleotides Porosity Portal vein structure Proteins RNA Rattus Research Research Support Risk Risk Factors Route Site Staging Tail Techniques Technology Therapeutic Tissues Transfection Translations Transplantation Treatment Efficacy Ultrasonic wave Ultrasonography Validation Veins Venous Viral Viral Genes Weight Work base commercial application dosage gene delivery system gene therapy hepatic vein improved innovation mouse model novel plasmid DNA pressure public health relevance research study response sound technological innovation therapeutic gene tool uptake

项目摘要

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.

描述（由申请人提供）：低密度脂蛋白（HDL）胆固醇的低水平是冠心病（CHD）的重要危险因素。 HDL胆固醇水平可预测他汀类药物治疗的患者的主要心血管事件。 LDL胆固醇水平低于70 mg的患者也观察到这种关系。研究表明，多核苷酸（例如DNA和RNA）可以传递到产生可以治疗性的细胞变化的细胞中。为了成功实现基因疗法，遗传材料与有效的递送工具一起提供局部治疗至关重要。编码以表达全部或部分蛋白的DNA可以直接通过转移到细胞中直接传递到生物体，然后将然后移植到生物体中。 Sonogene Corporation正在研究哺乳动物作为基因治疗手段的非病毒转染。提议开发一种靶向将DNA质粒转染到肝脏以增强APOA-I表达的方法。该赠款的要求是支持研究在肝脏中诱导ApoA-I基因表达的合适的非侵入性途径，以促进胆固醇代谢。我们建议将裸质粒ApoA-I DNA注入使用微球或微泡作为输送载体的血液中。肝脏中的毛细血管内皮细胞被延孕，并允许增强质粒对肝细胞的摄取。然后用超声波处理肝脏，破坏微球并引起肝内皮细胞的瞬时孔隙率，从而允许肝脏摄取和质粒DNA的表达。公共卫生相关性：高密度脂蛋白（HDL）胆固醇水平是冠心病的重要危险因素。低HDL胆固醇水平可预测患者的主要心血管事件。 Sonogene建议开发新型的超声技术，以提高HDL胆固醇水平，作为一种心脏保护策略。