Engineering Blood Vessels to Resist Atherosclerosis

描述（由申请人提供）：动脉粥样硬化引起心脏病发作、中风和外周血管疾病，是血管壁内发展的疾病过程的结果。该提案旨在开发基因疗法，将其递送到血管壁，以防止驱动动脉粥样硬化进展的生物过程。最终，通过在人类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的血管，因为它们对导致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，包括肯定会超出目前提案范围的工作。然而，目前的提案建立在主要研究者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。 有三个具体目标。第一个具体目标将测试基因治疗策略，通过增加脂质转运出血管壁或减少血管炎症来预防动脉粥样硬化。第二个目标包括将揭示使用辅助依赖性腺病毒载体在血管组织中可以实现的转基因表达的持续时间的实验。其他实验将测试用于增加来自这些载体的转基因表达的策略。第三个目标将检验辅助病毒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的相关炎症的假设。这些目标的成功将代表临床上有用的血管基因治疗的发展取得重大进展。 公共卫生相关性：目前动脉粥样硬化的三种治疗方法药物、血管成形术和旁路手术并没有消除与动脉粥样硬化相关的死亡和残疾。接受其中一种甚至所有三种治疗的患者仍然有心脏病发作、中风和肢体丧失的风险。开发和临床应用基因工程血管的方法和工具，使其不会发展为动脉粥样硬化，从而永远不会变窄或堵塞，这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。

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.