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

基本信息

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
项目类别：
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

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

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项目摘要

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.

项目摘要治疗阻塞性周围动脉疾病（PAD）患者的介入策略，影响8.5 由于更高的再狭窄率，美国的百万成年人失败了。再狭窄的重要过程是激活血管平滑肌细胞（VSMC）的迁移和增殖到内膜层阻塞动脉。在外围脉管系统中，大多数支架骨折（高达68％）由于过度动脉变形，导致骨折部位再狭窄并破坏药物释放动力学。在这些病例，气囊血管成形术通常是唯一的治疗选择，但是，结果不如支架。到克服垫子，药物涂层气球（DCB）的支架和气球血管成形术的局限性已成为一种替代方法。 DCB在本地运送药物，无需金属永久支架平台。迄今为止，DCB表现出急性成功，但未能显示长期术语治疗益处。但是，从机械上讲，DCB与DES的局限性相似，因为它们沉积了非 - 内膜表面上的特定抗增殖药物，从而不利地靶向内皮细胞并延迟重新皮层化。此外，DCB送出的抗增殖药物可以产生下游栓子，增加截肢风险。在此，我们建议制定一种新的策略，以提供平滑肌细胞直接靶向内侧治疗。我们的初步结果表明，VSMC-成功交付特定的RNA适体直接通过新型的灌注导管直接到动脉内侧。我们确认这新方法抑制新内膜的生长，并加速临床相关的临床前临床上的重新皮层化模型。总体而言，该提案将检验以下假设：灌注导管传递的RNA适体进入内侧将抑制新内膜生长，并加速血管愈合期间的再粘膜化过程。变化的条件以最大化RNA递送和使用灌注导管的保留，确定 VSMC的增殖和重新层化和识别适体中性抑制VSMC的机制将探索增长（特定目标1）。这些研究将使用新型的离体猪动脉来完成模仿周围动脉变形的循环系统。然后，我们将量化RNA保留，血管在猪损伤模型中重塑和重新内皮化（特定目标2）。最后，我们将评估在体内模型中患病的猪中处理的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疗法，抑制新内膜生长并促进血管康复。这种创新的突破将重新定义介入疗法在PAD治疗中的成功。