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Electro Gene Transfer for Coronary Artery Disease

冠状动脉疾病的电基因转移

基本信息

批准号：
7690306
负责人：
RICHARD HELLER
金额：
$ 37.76万
依托单位：
OLD DOMINION UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-30 至 2013-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7690306
关键词：
Adverse effects Angiogenic Factor Animal Model Area Biological Cardiac Cardiomyopathies Cardiovascular system Catheters Characteristics Chest Chronic Clinical Coronary Coronary Arteriosclerosis DNA DNA delivery Development Devices Disabled Persons Disease Disease model Effectiveness Electrodes Electroporation Evaluation Family suidae Feasibility Studies Fibroblast Growth Factor 2 Gene Delivery Gene Transfer Genes Genome Goals Health Heart Hemangioma Histocompatibility Testing Investigation Ischemia Kinetics Lead Long-Term Effects Mediating Methods Modeling Morbidity - disease rate Muscle Myocardium Organ Pathologic Phase Plasmids Principal Investigator Procedures Property Protocols documentation Research Research Personnel Safety Skin Surgeon System Techniques Testing Therapeutic Time Tissues Translations United States Vascular Diseases Vascular Endothelial Growth Factors Work angiogenesis base design experience gene delivery system gene therapy handicapping condition immunogenicity improved in vivo innovation minimally invasive mortality neovasculature non-viral gene delivery novel plasmid DNA programs prototype public health relevance response success technology/technique vector working group

项目摘要

DESCRIPTION (provided by applicant): The long-range goal of our research program is the development of more effective and safer gene-based therapies for a variety of diseases. The major focus of this study is the use of electrically mediated non-viral gene delivery for the induction of angiogenesis as a potential treatment of coronary artery disease and ischemic myocardial disease (CAD). The project is divided into two parts. A R21 feasibility study will be performed initially to determine if utilizing electroporation to deliver plasmids containing angiogenic factors to cardiac muscle can be successfully accomplished and to determine the electroporation characteristics and plasmid concentrations to identify a successful protocol. These steps are necessary to move forward to establish a therapeutic protocol. This portion of the study has three specific aims as follows: 1. to establish electroporation delivery parameters to obtain optimal expression following plasmid DNA delivery to cardiac muscle (CAD); 2. to develop a prototype catheter based electroporation delivery system and to determine the time that expression levels can be maintained; and 3. to determine if electroporation delivery of a plasmid encoding for VEGF can induce angiogenesis in the heart.. Successful completion of this portion of the project will establish delivery criteria to cardiac muscle. The results should demonstrate that the procedure can be performed safely and effectively. The second part of this project is a R33 developmental phase. This portion of the project will expand and extend the initial studies. Work will be focused on evaluating the potential of electroporation mediated gene therapy for treatment of coronary artery disease. The work will culminate in testing this approach in an appropriate ischemic model. The Specific Aims to be accomplished in this phase of the study are as follows: 1. to develop appropriate electrode systems, both catheter-based and for open chest procedures; 2. to evaluate gene delivery for CAD with respect to long-term effects and vessel development; and 3. to evaluate the delivery protocol in an appropriate disease model. The electroporation delivery characteristics and protocols are anticipated to be successful based on the work of this group in other organs and tissues. The described protocol is a major advancement of proven techniques to a new species model and a new pathologic state. By including an experienced cardiovascular surgeon and renowned clinical cardiac electrophysiologist, this inter-disciplinary team is extraordinarily capable of moving into a new area of investigation utilizing and expanding current techniques and technology to plan and implement this unique, novel, and innovative protocol with high likelihood of success. This will result in an innovative method for delivery of plasmids encoding for angiogenic factors to the heart for the treatment of chronic vascular disease. Public Health Relevance: Coronary artery disease is a growing health problem in the United States and the world. The development of new or improvement of existing therapeutic approaches is critical to reducing the morbidity and mortality of this disease. Development of a non-viral gene delivery system for factors that will facilitate revascularization of ischemic tissue would be an important advance. The work proposed in this study will evaluate electroporation as a means to deliver plasmids encoding angiogenic factors directly to ischemic tissue as a potential therapy.

描述(由申请人提供)：我们研究计划的长期目标是为各种疾病开发更有效和更安全的基于基因的疗法。这项研究的主要焦点是使用电介导的非病毒基因传递来诱导血管生成，作为一种潜在的治疗冠状动脉疾病和缺血性心肌病(CAD)的方法。该项目分为两个部分。最初将进行R21可行性研究，以确定是否可以成功地利用电穿孔将含有血管生成因子的质粒输送到心肌，并确定电穿孔特性和质粒浓度以确定成功的方案。这些步骤是向前推进以建立治疗方案所必需的。这部分研究有三个具体的目的：1.建立电穿孔输送参数，以获得最佳的表达载体DNA到心肌(CAD)；2.开发基于导管的电穿孔输送系统，并确定表达水平维持的时间；以及3.确定电穿孔输送编码血管内皮生长因子的质粒是否能诱导心脏血管生成。该项目这一部分的成功完成将建立对心肌的输送标准。结果应该证明，该手术可以安全有效地进行。该项目的第二部分是R33开发阶段。该项目的这一部分将扩大和延长初步研究。工作的重点将是评估电穿孔介导的基因疗法治疗冠状动脉疾病的潜力。这项工作最终将在适当的缺血模型中测试这种方法。在这一阶段的研究中要实现的具体目标如下：1.开发合适的电极系统，包括基于导管的和用于开胸手术的电极系统；2.从长期效果和血管发育的角度评估CAD的基因输送；以及3.在适当的疾病模型中评价输送方案。基于该小组在其他器官和组织中的工作，预计电穿孔传递特征和方案将取得成功。所描述的方案是成熟技术在新的物种模型和新的病理状态方面的重大进展。通过包括一位经验丰富的心血管外科医生和著名的临床心脏电生理学家，这个跨学科的团队非常有能力进入一个新的研究领域，利用和扩展当前的技术和技术来规划和实施这一独特、新颖和创新的方案，并具有很高的成功可能性。这将导致一种创新的方法，将编码血管生成因子的质粒输送到心脏，用于治疗慢性血管疾病。公共卫生相关性：在美国和全世界，冠状动脉疾病是一个日益严重的健康问题。开发新的或改进现有的治疗方法对于减少这种疾病的发病率和死亡率至关重要。开发一种非病毒基因传递系统，用于促进缺血组织血管重建的因子，将是一个重要的进展。这项研究中提出的工作将评估电穿孔作为一种潜在的治疗方法将编码血管生成因子的质粒直接输送到缺血组织的方法。