A Novel Endovascular Approach to Remove Atherosclerotic Plaque Lesions In Situ

摘要 继发于动脉粥样硬化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 或者不部署刚性的、不合规的金属支架。然而，该技术未能消除 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 再狭窄率。 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 动脉再狭窄。因此，本研究的目标是开发一种新颖的血管内技术 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 墙。我们的范式转换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 专为安全消化动脉粥样硬化斑块而定制。鉴于大多数动脉粥样硬化斑块由 我们假设胶原蛋白、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。避免在我们的产品中使用弹性蛋白酶 溶液限制了牙菌斑对弹性层的消化。凭借我们的多学科研究团队，我们 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。我们有 证明可以有效消化切除的人颈动脉动脉粥样硬化斑块以及斑块 位于完整的人类股浅动脉内。我们已经在非动脉粥样硬化患者中评估了我们的方法 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 减少斑块而不诱发血栓形成或动脉瘤变性。鉴于可行性和承诺 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 是有保证的，并将带来治疗人类动脉粥样硬化的创新临床疗法。因此， 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可重复性。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”。

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.