A Novel Endovascular Approach to Remove Atherosclerotic Plaque Lesions In Situ

一种原位去除动脉粥样硬化斑块病变的新型血管内方法

基本信息

批准号：
10084300
负责人：
Melina Rae Kibbe
金额：
$ 71.17万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-01 至 2021-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10084300
关键词：
Affect Aneurysm Angiography Animal Model Area Arterial Fatty Streak Arteries Atherosclerosis Balloon Angioplasty Balloon Occlusion Blood Blood Vessels Calcium Cardiovascular Diseases Carotid Arteries Catheters Cause of Death Cells Clinical Coagulation Process Collagen Complement Activation Custom Data Development Digestion Dilatation - action Dissection Distal Elastases Embolism Endothelium FDA approved Family suidae Fibrin Goals Health Human Hyperplasia Immunohistochemistry In Situ In Situ Lesion Individual Inflammation Inflammatory Intervention Knowledge Lead Life Lipids Longitudinal Studies Mechanics Metals Methods Mission Outcome Measure Phase I Clinical Trials Platelet aggregation Procedures Proteoglycan Research Personnel Safety Secondary to Smooth Muscle Myocytes Sonication Stents Superficial Femoral Artery Techniques Technology Testing Thick Thrombosis Time Trauma Tumor Debulking Ultrasonography United States United States National Institutes of Health Vasomotor base clinically relevant conventional therapy disability efficacy study first-in-human heat injury iliac artery improved outcome in vivo Model innovation medical specialties multidisciplinary new technology non-compliance novel optimal treatments porcine model pre-clinical restenosis safety study sex systemic inflammatory response targeted agent time use

项目摘要

SUMMARY Cardiovascular disease secondary to atherosclerosis is the leading cause of death in the United States. Current percutaneous vascular interventions that treat severe atherosclerosis require inflation of a balloon with or without deployment of a rigid, non-compliant metal stent. Yet, this technique fails to remove the atherosclerotic plaque burden and causes mechanical trauma to the arterial wall, resulting in significant restenosis rates. FDA-approved plaque debulking technologies do exist and are used in the clinical arena. However, to debulk the plaque, each of these therapies induces some form of mechanical or thermal injury to the vessel wall, which ultimately stimulates the development of neointimal hyperplasia and results in significant arterial restenosis. Therefore, the goal of this study is to develop a novel endovascular technology to reduce atherosclerotic plaque burden without inducing thermal or mechanical trauma to the arterial wall. Our paradigm-shifting technology is based on a safe method of digesting atherosclerotic plaque in situ through the use of a double occlusion balloon catheter, sonication wire, and a highly customized solution tailored to safely digest atherosclerotic plaque. Given that most atherosclerotic plaques are composed of collagen, fibrin, lipids, proteoglycans, inflammatory cells, smooth muscle cells, and calcium, we hypothesize that a digestion solution containing agents that target these plaque components will dissolve and digest the plaque in situ within a clinically relevant time frame. Avoidance of the use of elastases in our solution limits digestion of the plaque to the elastic lamina. With our multidisciplinary team of investigators, we have already demonstrated the feasibility and initial safety of our approach through preliminary data. We have demonstrated effective digestion of excised human carotid artery atherosclerotic plaques as well as the plaque inside intact human superficial femoral arteries. We have evaluated our approach in a non-atherosclerotic porcine model in vivo and showed that our therapy did not injure the arterial wall, was limited to the internal elastic lamina, and did not result in dissections or aneurysm formation, suggesting that our therapy is safe. Lastly, we evaluated our approach in an atherosclerotic porcine model and demonstrated initial efficacy at reducing plaque without inducing thrombosis or aneurysmal degeneration. Given the feasibility and promise of these preliminary data, we believe further scientific exploration and development of this novel technology is warranted and will lead to an innovative clinical therapy for the treatment of atherosclerosis in humans. Thus, the overall objective of this proposal is to robustly evaluate the safety, efficacy, durability, and repeatability of this therapy in a preclinical porcine animal model of atherosclerosis. Successful completion of these studies will directly lead to an FDA application for a first-in-human Phase 1 clinical trial, and is thus highly aligned with the mission of the National Institutes of Health to “enhance health, lengthen life, and reduce illness and disability” through the application of new knowledge.

概括动脉粥样硬化继发的心血管疾病是美国的主要原因。目前治疗严重动脉粥样硬化的经皮血管介入治疗需要用气球充气或者没有部署刚性的、不合规的金属支架然而，该技术无法去除支架。动脉粥样硬化斑块负担并对动脉壁造成机械损伤，导致显着的 FDA 批准的斑块减灭技术确实存在并应用于临床领域。然而，为了减少斑块的体积，这些疗法中的每一种都会引起某种形式的机械或热损伤血管壁，最终刺激新内膜增生的发展，并导致显着的因此，本研究的目标是开发一种新型血管内技术来治疗动脉再狭窄。减少动脉粥样硬化斑块负担，而不会对动脉造成热或机械损伤我们的范式转变技术基于一种原位消化动脉粥样硬化斑块的安全方法。通过使用双闭塞球囊导管、超声处理线和高度定制的解决方案鉴于大多数动脉粥样硬化斑块由以下物质组成，专为安全消化动脉粥样硬化斑块而设计。我们捕获了胶原蛋白、纤维蛋白、脂质、蛋白聚糖、炎症细胞、平滑肌细胞和钙含有针对这些牙菌斑成分的试剂的消化溶液会溶解并在临床相关的时间范围内原位消化斑块，避免在我们的实验中使用弹性蛋白酶。通过我们的多学科研究团队，我们的解决方案将斑块的消化限制在弹性层上。已经通过初步数据证明了我们方法的可行性和初步安全性。对切除的人颈动脉的有效消化证明了动脉粥样硬化斑块以及斑块我们已经在非动脉粥样硬化的情况下评估了我们的方法。猪体内模型表明我们的治疗不会损伤动脉壁，仅限于内部弹力层，并且没有导致夹层或动脉瘤形成，表明我们的治疗是安全的。最后，我们在动脉粥样硬化猪模型中评估了我们的方法，并证明了初步疗效鉴于其可行性和前景，减少斑块而不诱发血栓形成或动脉瘤变性。这些初步数据，我们相信对这项新技术的进一步科学探索和发展是有必要的，并将带来治疗人类动脉粥样硬化的创新临床疗法。该提案的总体目标是强有力地评估安全性、有效性、耐久性和该疗法在临床前猪动脉粥样硬化动物模型中的重复性取得了成功。这些研究的完成将直接导致 FDA 申请首次人体 1 期临床试验，因此与美国国立卫生研究院“增强健康、延长寿命、通过应用新知识来减少疾病和残疾”。