Intracoronary MRI-Enhanced Gene Therapy

描述（由申请人提供）：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人数的60%，给医疗保健系统带来了巨大的负担。尽管药物涂层支架植入术已成为冠心病的主要干预手段，但FDA最近的警告表明，所有接受药物涂层支架植入术的患者发生血栓的风险增加，许多接受药物涂层支架植入术的患者有心脏病发作和死亡的风险。因此，有必要探索管理CAD的替代方法。基因疗法在治疗CAD病因方面显示出巨大的潜力。近年来，在一项为期4年的NIH R01资助的支持下，我们已经成功地证明了一种新概念的血管内磁共振成像/射频（RF）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)冠状动脉内磁共振成像/射频加热系统，同时生成基因/支架靶向冠状动脉的高分辨率磁共振成像和冠状动脉中磁共振/射频增强的基因转导/表达；(b)冠状动脉内MR/ rf增强基因治疗支架内狭窄。这些新技术将在一系列的临床前研究中得到验证，这些研究将在接近人类大小的动物、家猪和患有CAD的尤卡坦迷你猪的冠状动脉中进行，这将有助于这些新技术进一步从实验室到床边的转化。我们坚信，该项目的成功将为我们的长期目标奠定基础，即应用基于核磁共振的血管基因疗法有效治疗人类CAD。

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.