Electro Gene Transfer for Coronary Artery Disease

冠状动脉疾病的电基因转移

• 批准号: 7496819
• 负责人: RICHARD HELLER
• 金额: $ 37.78万
• 依托单位: OLD DOMINION UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-30 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7496819
• 关键词: Adverse effects; Angiogenic Factor; Animal Model; Area; Biological; Cardiac; Cardiomyopathies; Cardiovascular system; Catheters; Characteristics; Chest; Chronic; Clinical; Condition; Coronary; Coronary Arteriosclerosis; DNA; DNA delivery; Development; Devices; Disabled Persons; Disease; Disease model; Disease regression; Effectiveness; Electrodes; Electroporation; Evaluation; Family suidae; Feasibility Studies; Fibroblast Growth Factor 2; Gene Delivery; Gene Transfer; Genes; Genome; Goals; Health; Heart; Hemangioma; Histocompatibility Testing; Invasive; Investigation; Ischemia; Kinetics; Lead; Localized; Long-Term Effects; Mediating; Methods; Modeling; Morbidity - disease rate; Muscle; Myocardium; Organ; Pathologic; Phase; Plasmids; Principal Investigator; Procedures; Property; Protocols documentation; Public Health; Range; Research; Research Personnel; Safety; Skin; Surgeon; System; Techniques; Testing; Therapeutic; Time; Tissues; Translations; Tumor-Associated Vasculature; United States; Vascular Diseases; Vascular Endothelial Growth Factors; Work; angiogenesis; base; concept; design; experience; gene delivery system; gene therapy; handicapping condition; immunogenicity; improved; in vivo; innovation; mortality; non-viral gene delivery; novel; plasmid DNA; programs; prototype; response; success; technology/technique; vector

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开发针对各种疾病的更有效和更安全的基因疗法。本研究的主要焦点是使用电介导的非病毒基因递送诱导血管生成作为冠状动脉疾病和缺血性心肌疾病（CAD）的潜在治疗。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完成利用电穿孔将含有血管生成因子的质粒递送至心肌，并确定电穿孔特征和质粒浓度，以确定成功的方案。这些步骤对于制定治疗方案是必要的。本部分的研究有以下三个具体目标：1.建立电穿孔递送参数以在质粒DNA递送至心肌（CAD）后获得最佳表达; 2.开发基于原型导管的电穿孔递送系统并确定表达水平可以维持的时间;和3.以确定编码VEGF的质粒的电穿孔递送是否可以诱导心脏中的血管生成。成功完成该部分项目将确立心肌输送标准。结果应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扩展初步研究。工作将集中在评估电穿孔介导的基因治疗冠心病的潜力。这项工作最终将在适当的缺血模型中测试这种方法。本阶段研究的具体目标如下：1.开发适当的电极系统，包括基于导管的电极系统和用于开胸手术的电极系统; 2.评估CAD的基因递送的长期效果和血管发育;以及3.以在适当的疾病模型中评估递送方案。基于该小组在其他器官和组织中的工作，预计电穿孔递送特性和方案将是成功的。所描述的协议是一个重大的进步，证明技术的一个新的物种模型和一个新的病理状态。通过包括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计划和实施这个独特的，新颖的和创新的方案，成功的可能性很高。这将产生一种将编码血管生成因子的质粒递送到心脏以治疗慢性血管疾病的创新方法。 公共卫生相关性：冠状动脉疾病是美国和世界上日益严重的健康问题。开发新的治疗方法或改进现有的治疗方法对于降低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的因素，将有助于缺血组织的血管重建将是一个重要的进步。本研究中提出的工作将评估电穿孔作为一种手段，将编码血管生成因子的质粒直接递送到缺血组织作为一种潜在的治疗方法。