Intracoronary MRI-Enhanced Gene Therapy

描述(申请人提供)：动脉粥样硬化性心血管疾病仍然是美国死亡的主要原因。冠状动脉疾病(CAD)占动脉粥样硬化性心血管疾病死亡的60%，给医疗保健系统带来了巨大的负担。尽管药物涂层支架已成为冠心病的主要干预手段，但FDA最近的警告表明，所有接受药物涂层设备的患者都有更高的血栓风险，许多接受设备的患者有心脏病发作和死亡的风险。因此，探索管理CAD的替代方法是至关重要的。基因治疗在治疗冠心病的病因方面显示出巨大的潜力。近年来，在NIH R01为期4年的拨款支持下，我们成功地证明了一种新概念血管内磁共振成像/射频增强血管基因治疗的原理。这项新技术现在可以应用于CAD的治疗。将这项新技术扩展到冠状动脉，我们将探索两项新的技术发展，包括(A)冠状动脉内MR成像/RF加热系统，以同时产生针对基因/支架靶向的冠状动脉的高分辨率MR成像以及MR/RF增强的冠状动脉内基因转导/表达；以及(B)冠状动脉内MR/RF增强的支架内狭窄的基因治疗。这些新技术将在对近乎人类大小的动物、家猪和患有CAD的尤卡坦小型猪的冠状动脉进行的一系列临床前研究中得到验证，这将促进这些新技术从实验台到床边的进一步转化。我们坚信，该项目的成功将为我们应用基于MR的血管基因疗法有效治疗人类冠心病的长期目标奠定基础。 项目简介：动脉粥样硬化性心血管疾病(ACD)仍然是美国主要的死亡原因，给医疗保健系统带来了巨大的负担。时至今日，ACD的有效治疗方法尚未建立。在目前的提案中，我们将探索一种新的技术-基于冠状动脉内MRI的射频(RF)增强的ACD基因治疗。这一项目的成功将为今后利用基于监测和监测的方式对非传染性疾病进行全球综合管理开辟新的途径。

DESCRIPTION (provided by applicant): Atherosclerotic cardiovascular disease remains the leading cause of mortality in the United States. Coronary artery disease (CAD) comprises 60% of deaths from atherosclerotic cardiovascular disease and places an enormous burden on the healthcare system. Although drug-coated-stenting has become the primary intervention of CAD, recent warning by the FDA has indicated that all patients receiving the drug-coated devices are at a heightened risk for blood clots, and that many patients receiving the devices are at risk for heart attacks and death. Thus, it is essential to explore alternative approaches to manage CAD. Gene therapy shows great potential for treatment of the causes of CAD. In recent years, supported by a 4-year NIH R01 grant, we have successfully proven the principle of a novel concept intravascular MR- imaging/radiofrequency (RF)-enhanced vascular gene therapy. This new technology can now be applied to the treatment of CAD. Extending this new technology to coronary arteries, we will explore two novel technical developments, including (a) an intracoronary MR-imaging/RF-heating system to simultaneously generate high-resolution MR imaging of the gene/stent-targeted coronary arteries and MR/RF-enhanced gene transduction/expression in the coronary arteries; and (b) intracoronary MR/RF-enhanced gene therapy of in-stent stenosis. These novel techniques will be validated in a series of preclinical studies in the coronary arteries of near-human-sized animals, domestic pigs and Yucatan miniature pigs with CAD, which should facilitate the further translation of these novel techniques from the benchside to the bedside. We firmly believe that the success of this project will establish the groundwork for our longer-term goal of applying MR-based vascular gene therapy to efficiently treat CAD in humans. Project Narrative: Atherosclerotic cardiovascular disease (ACD) remains the leading cause of mortality in the United States, and places an enormous burden on the healthcare system. To day, the method for efficient treatment of ACD has not been established. In the current proposal, we will explore a novel technology - intracoronary MRI-based, radiofrequency (RF)-enhanced gene therapy of ACD. The success of this project should open up new avenues for the future global comprehensive management of ACD using MR-based modalities.