MicroRNA-Based, Cell-Selective Therapy for Coronary Artery Disease

 描述：心血管疾病(CVD)是全球主要的死亡原因。尽管支架治疗在过去20年中取得了重大的技术进步，但再狭窄和血栓形成(主要是晚期和超晚期)仍然是导致支架相关发病率和死亡率的主要因素。到目前为止，支架治疗是非选择性的，影响血管平滑肌细胞和内皮细胞，并严格进行不利的取舍。药物洗脱支架(DES)有效地抑制了新生内膜的生长，但代价是支架支架覆盖率低，内皮功能不佳。这种无法提供细胞选择性的能力 治疗阻碍了经皮介入治疗的进展。作为回应，我们开发了一种基于创新的microRNA(MiRNA)的细胞选择性治疗方法，在已建立的正常大鼠球囊血管成形术模型上取得了显著效果。这种新疗法选择性地抑制新生内膜增生和炎症，同时促进血管再内皮化，降低高凝状态，并将内皮依赖性血管扩张反应恢复到与未损伤对照难以区分的水平。为了将这一治疗策略转化为临床环境，并更好地反映接受介入治疗的患者的状况，我们的目标是在已建立的动脉粥样硬化兔模型中测试我们的策略的有效性。在三个特定目标中，我们将评估这种基于miRNA的细胞选择性疗法与DES相比在(1)抑制动脉粥样硬化形成；(2)促进动脉粥样硬化回归；(3)抑制支架内再狭窄和恢复内皮-支架覆盖方面的能力。这些研究具有巨大的治疗意义，它们的成功完成将推动细胞选择性治疗的发展，并对心血管干预的临床实践产生重大影响，以提高心血管疾病患者的预期寿命。

 DESCRIPTION: Cardiovascular disease (CVD) is the leading cause of death worldwide. Despite the major technological advances in stent therapy over the past two decades, restenosis and thrombosis (primarily late and very late) remain principal factors contributing to stent-associated morbidity and mortality rates. To date, stent therapies are non-selective, affecting vascular smooth muscle cells and endothelial cells alike and exacting unfavorable trade-offs. Drug-eluting stents (DES) effectively suppress neointimal growth, but at the expense of poor stent strut coverage with incompetent endothelium. This inability to deliver cell-selective therapy has hindered progress in percutaneous interventions. In response, we have developed an innovative microRNA (miRNA)- based, cell-selective therapy that achieved striking results in an established normal rat model of balloon angioplasty. This novel therapy selectively inhibited neointimal hyperplasia and inflammation while simultaneously promoting vessel reendothelialization, reducing hypercoagulability and restoring the endothelium-dependent vasodilatory response to levels indistinguishable from uninjured control. To translate this therapeutic strategy to a clinical setting, and better reflect the condition of patients that undero interventional procedures, we aim to test the efficacy of our strategy in a rabbit model of established atherosclerosis. In three specific aims, we will evaluate the ability of this miRNA-based, cell-selective therapy to (1) inhibit atherogenesis; (2) promote atheroregression; and (3) inhibit in-stent restenosis and restore endothelial-strut coverage when compared against DES. These studies have tremendous therapeutic implications, and their successful completion will advance the development of cell-selective therapies and significantly impact the clinical practice of cardiovascular intervention to improve the life expectancy of CVD patients.