Local delivery of smooth muscle cell targeted aptamer to inhibit neointimal growth and accelerate vascular healing

局部递送平滑肌细胞靶向适配体以抑制新内膜生长并加速血管愈合

• 批准号: 10188528
• 负责人: Saami K Yazdani
• 金额: $ 51.79万
• 依托单位: WAKE FOREST UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10188528
• 关键词: Acute; Address; Adherence; Adult; Affect; Agonist; Amputation; Arteries; Balloon Angioplasty; Binding; Bioreactors; Blood Vessels; Cardiovascular system; Catheters; Cell surface; Cells; Clinical; Deposition; Devices; Disease; Disease model; Drug usage; Embolism; Endothelial Cells; Endothelium; Family suidae; Fluid Balance; Foundations; Fracture; Growth; Harvest; Human; Inferior; Inflammation; Injury; Intervention; Lesion; Leukocytes; Lipids; Liquid substance; Medial; Methods; Modeling; Nucleic Acids; Outcome; Patients; Perfusion; Peripheral; Peripheral Vascular Diseases; Peripheral arterial disease; Pharmaceutical Preparations; Platelet aggregation; Positioning Attribute; Pre-Clinical Model; Process; Proliferating; Property; RNA; RNA delivery; Risk; Safety; Site; Smooth Muscle Myocytes; Stents; Surface; System; Techniques; Testing; Therapeutic; Therapeutic Intervention; Time; Tissues; Vascular Diseases; Vascular Endothelium; Vascular Smooth Muscle; Work; antiproliferative drugs; aptamer; base; cell growth; clinically relevant; drug release kinetics; healing; in vivo; in vivo Model; innovation; metallicity; migration; novel; novel strategies; oxidation; porcine model; prevent; response; restenosis; standard care; standard of care; success; targeted treatment; three dimensional structure; vascular smooth muscle cell migration; vascular smooth muscle cell proliferation

Project Summary Interventional strategies to treat patients with obstructive peripheral artery disease (PAD), which affects 8.5 million adults in the US, are failing due to high rates of restenosis. A vital process in restenosis is the activation of vascular smooth muscle cells (VSMCs), resulting in their migration and proliferation into the intimal layer, re- occluding the artery. In the peripheral vasculature, the majority of stents fracture (up to 68%) due to excessive arterial deformation, resulting in restenosis at the fracture sites and disrupting drug release kinetics. In these cases, balloon angioplasty is often the only treatment option, however, outcomes are inferior to stents. To overcome the limitations of stents and balloon angioplasty in the treatment of PAD, drug coated balloons (DCBs) have emerged as an alternative approach. DCBs deliver drugs locally onto the arterial wall without the need of a metallic permanent stent platform. To date, DCBs have shown acute success but have failed to show long- term therapeutic benefit. Mechanistically though, DCBs have similar limitations to DES in that they deposit non- specific anti-proliferative drugs on the intimal surface, thereby adversely targeting endothelial cells and delaying re-endothelialization. Additionally, anti-proliferative drugs delivered by DCBs can produce downstream emboli, increasing amputation risks. Herein, we propose to develop a new strategy that delivers smooth muscle cell targeted therapy directly to the medial layer. Our preliminary results demonstrate successful delivery of VSMC- specific RNA aptamers directly to the arterial medial layer via a novel perfusion catheter. We confirm that this novel approach inhibits neointimal growth and accelerates re-endothelialization in a clinically relevant pre-clinical model. Overall, this proposal will test the hypothesis that RNA aptamer delivered by a perfusion catheter directly into the medial layer will inhibit neointimal growth and accelerate re-endothelialization during the vascular healing process. Varying conditions to maximize RNA delivery and retention using the perfusion catheter, determining VSMC proliferation and re-endothelization and identifying mechanism(s) of aptamer-medial inhibition of VSMC growth will be explored (Specific Aim 1). These studies will be accomplished using a novel ex vivo porcine artery circulatory system that mimics peripheral artery deformation. We will then quantify RNA retention, vessel remodeling and re-endothelialization in a porcine injury model (Specific Aim 2). Finally, we will evaluate the vascular response and healing of the treated RNA arteries in a diseased porcine in vivo model (Specific Aim 3). Through these aims, we will generate a targeted therapy that inhibits neointimal growth and promotes vascular healing. This innovative break-through will redefine the success of interventional therapy in the treatment of PAD.

项目摘要 影响8.5的阻塞性外周动脉疾病(PAD)患者的介入策略 在美国，由于高再狭窄率，数以百万计的成年人正在失败。再狭窄的一个重要过程是激活 血管平滑肌细胞(VSMCs)的迁移和增殖，使其重新进入内膜层。 阻塞动脉。在外周血管系统中，大多数支架(高达68%)因过度使用而断裂 动脉变形，导致骨折部位再狭窄，扰乱药物释放动力学。在这些 在某些情况下，球囊血管成形术往往是唯一的治疗选择，然而，结果不如支架。至 克服支架和球囊成形术在PAD、药物涂层球囊治疗中的局限性 已经成为一种替代方法。DCB将药物局部输送到动脉壁上，而不需要 一种金属永久性支架平台。到目前为止，DCB取得了巨大的成功，但未能表现出长期的 长期治疗效益。然而，从机制上讲，DCB具有与DES类似的限制，因为它们将非 内膜表面的特定抗增殖药物，从而不利地靶向内皮细胞并延迟 再内皮化。此外，DCB提供的抗增殖药物可能会产生下游血栓， 截肢风险增加。在此，我们建议开发一种新的策略，将平滑肌细胞 直接向内侧层进行靶向治疗。我们的初步结果表明VSMC成功交付- 通过一种新型的灌流导管将特定的RNA适配子直接连接到动脉中层。我们确认这一点 新的方法抑制新生内膜生长并加速临床前相关临床前的再内皮化 模特。总体而言，这项提议将检验rna适配子通过灌流导管直接输送的假设。 进入中层会抑制血管愈合过程中新生内膜的生长并加速再内皮化。 进程。改变条件以最大限度地利用灌流导管传递和保留RNA，确定 血管平滑肌细胞增殖、再内皮化及适体-中介性抑制的识别机制(S) 将探索成长(具体目标1)。这些研究将使用一种新的体外猪动脉来完成 模拟外周动脉变形的循环系统。然后我们将量化RNA的保留量，容器 猪损伤模型中的重塑和再内皮化(特定目标2)。最后，我们将评估 在病猪体内模型中经处理的RNA动脉的血管反应和愈合(特定目标3)。 通过这些目标，我们将产生一种靶向治疗，抑制新生内膜生长并促进血管 治愈。这一创新突破将重新定义介入治疗在PAD治疗中的成功。