Engineering Blood Vessels to Resist Atherosclerosis

改造血管以抵抗动脉粥样硬化

• 批准号: 7148722
• 负责人: David A Dichek
• 金额: $ 51.57万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7148722
• 关键词: Adenoviridae; apolipoproteins; atherosclerosis; atherosclerotic plaque; biotechnology; blood vessel transplantation; cardiovascular disorder prevention; cholesterol; gene delivery system; gene expression; gene therapy; helper virus; inflammation; interleukin 10; laboratory rabbit; lipid transport; nonhuman therapy evaluation; transfection /expression vector

DESCRIPTION (provided by applicant): Atherosclerosis causes heart attacks, strokes, and peripheral vascular disease, and is a consequence of disease processes that develop within the blood vessel wall. This proposal seeks to develop gene therapy, delivered to the blood vessel wall, that prevents the biological processes that drive the progression of atherosclerosis. Eventually, by expressing anti-atherosclerotic transgenes in human vascular tissue, this approach may yield blood vessels that remain disease-free indefinitely because they are resistant to the underlying biological processes that cause atherosclerosis. This is an ambitious objective, including work that is certain to extend beyond the current proposal. However, the current proposal builds on several years of progress in the laboratory of the Principal Investigator and sets forth the next critical steps towards gene therapy for atherosclerosis. There are three specific aims. The first specific aim will test gene-therapy strategies that prevent atherosclerosis by increasing lipid transport out of the vessel wall or by decreasing vascular inflammation. The second aim includes experiments that will reveal the duration of transgene expression that can be achieved in vascular tissue using helper-dependent adenoviral vectors. Other experiments will test strategies for increasing transgene expression from these vectors. The third aim will test the hypothesis that helper- dependent adenoviral vectors will provide durable transgene expression with minimal associated inflammation in vein grafts. Success in these aims will represent significant progress towards development of clinically useful vascular gene therapy. PUBLIC HEALTH RELEVANCE: The three current therapies for atherosclerosis-drugs, angioplasty, and bypass surgery-have not eliminated death and disability associated with atherosclerosis. Patients receiving one or even all three of these therapies continue to be at risk for heart attacks, strokes, and limb loss. Development and clinical application of methods and tools to genetically engineer blood vessels so that they do not develop atherosclerosis-and therefore never become narrowed or clogged-would have a major impact on the morbidity, mortality, and health-care costs of cardiovascular disease.

描述（由申请人提供）：动脉粥样硬化会导致心脏病、中风和外周血管疾病，并且是血管壁内发生的疾病过程的结果。该提案旨在开发针对血管壁的基因疗法，以防止驱动动脉粥样硬化进展的生物过程。最终，通过在人体血管组织中表达抗动脉粥样硬化转基因，这种方法可能会产生无限期保持无病状态的血管，因为它们对引起动脉粥样硬化的潜在生物过程具有抵抗力。这是一个雄心勃勃的目标，包括肯定会超出当前提案范围的工作。然而，当前的提案建立在首席研究员实验室几年的进展基础上，并提出了动脉粥样硬化基因治疗的下一个关键步骤。 具体目标有三个。第一个具体目标是测试基因治疗策略，通过增加脂质从血管壁的转运或减少血管炎症来预防动脉粥样硬化。第二个目标包括揭示利用辅助依赖性腺病毒载体在血管组织中实现转基因表​​达持续时间的实验。其他实验将测试增加这些载体转基因表达的策略。第三个目标将检验辅助依赖性腺病毒载体将在静脉移植物中提供持久的转基因表达和最小化相关炎症的假设。这些目标的成功将代表着临床有用的血管基因疗法的发展取得了重大进展。 公众健康相关性：目前治疗动脉粥样硬化的三种疗法——药物、血管成形术和搭桥手术——并没有消除与动脉粥样硬化相关的死亡和残疾。接受其中一种甚至全部三种疗法的患者仍然面临心脏病、中风和肢体丧失的风险。对血管进行基因改造的方法和工具的开发和临床应用，使血管不会发生动脉粥样硬化，从而永远不会变窄或堵塞，将对心血管疾病的发病率、死亡率和医疗费用产生重大影响。