Improved Adventitial Sirolimus Therapy for Peripheral Artery Restenosis

改善外周动脉再狭窄的外膜西罗莫司疗法

• 批准号: 7909464
• 负责人: Kirk Seward
• 金额: $ 21.74万
• 依托单位: MERCATOR MEDSYSTEMS, INC.
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-15 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7909464
• 关键词: Address; Affect; Albumins; American; Amputation; Angioplasty; Arteries; Atherectomy; Atherosclerosis; Balloon Angioplasty; Binding; Blood Circulation; Blood Vessels; Bypass; Catheters; Cell Volumes; Clinical; Clinical Research; Clinical Trials; Combined Modality Therapy; Coronary; Coronary artery; Couples Therapy; Data; Deposition; Devices; Diabetes Mellitus; Disadvantaged; Dissection; Distal; Dose; Drug Delivery Systems; Drug Formulations; Drug Kinetics; Drug usage; Epidemic; FDA approved; Family suidae; Foreign Bodies; Gangrene; Goals; Ground Substance; Harvest; Healed; Human; Hyperplasia; Implant; In Vitro; Incidence; Individual; Infusion procedures; Injection of therapeutic agent; Injury; Insulin Resistance; Intervention; Kidney; Kinetics; Lead; Leg; Legal patent; Limb structure; Lower Extremity; Medial; Metals; Methods; Modeling; Morbidity - disease rate; Needles; Obesity; Operative Surgical Procedures; Pain; Patients; Pericytes; Peripheral; Peripheral arterial disease; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacotherapy; Phase; Phenotype; Pilot Projects; Placebos; Play; Prevalence; Prevention; Proliferating; Public Health; Rana catesbeiana; Recovery; Research; Role; Sample Size; Sampling; Sirolimus; Slide; Smooth Muscle Myocytes; Societies; Stenosis; Stents; Structure of popliteal artery; Superficial Femoral Artery; Surface; Techniques; Testing; Therapeutic; Time; Tissues; Toxic effect; Translating; Tunica Adventitia; Ulcer; Vascular Diseases; Vascular remodeling; Walking; aging population; animal data; base; commercialization; demographics; dosage; effective therapy; femoral artery; fibrous protein; healing; implantation; improved; innovation; nanoparticle; novel; post intervention; preclinical study; prevent; public health relevance; renal artery; restenosis; success

DESCRIPTION (provided by applicant): Peripheral artery disease (PAD) affects 9 to 12 million Americans [1] and 1.5 million will require an intervention (407,400 receive bypass or amputation; 1,080,000 receive angioplasty, stent or atherectomy) each year [3]. Unfortunately, only one-third of patients have a patent artery one year after balloon angioplasty of the femoral artery [4]. Bare metal stents [5-7] have eliminated elastic recoil and flow-limiting dissections but have not significantly impacted restenosis due to intimal hyperplasia [3, 8-10]. Indeed, stents placed in the femoro- popliteal segment provide patency rates of only 54-63% at 1 year and 28-55% at 2 years [5, 7, 11-12], and drug eluting stents have fared no better than bare stents in eliminating restenosis [13-15]. Recently, use of drug eluting balloons in the peripheral artery has shown potential to improve patency without the need to implant stents [16]. The kinetics of luminal-based therapy (drug-eluting balloons and stents) place the maximal concentration of drug at the luminal-wall interface. This has the distinct disadvantage of hindering healing and re-endothelialization of the vessel. Recent data suggests that the adventitia plays an important role in intimal hyperplasia, contributing to both neointimal cell volume and adverse remodeling. We propose to deliver sirolimus, a well-known anti-restenotic agent in a novel nanoparticle formulation, directly into the vascular adventitia through a percutaneous catheter at the time of angioplasty. This method avoids foreign body implantation and creates a high concentration in the adventitia and a lower concentration at the luminal surface. Mercator MedSystems has developed a catheter that slides a single needle through the vessel wall when a balloon is inflated, allowing direct therapeutic access to the adventitia. Adventitial delivery with this catheter leads to cylindrical deposition of drugs around the vessel, creating a natural drug-eluting reservoir. In Specific Aim 1 we plan to assess the magnitude of effect of three different sirolimus doses as compared to placebo in a porcine model of peripheral artery restenosis. We will choose a therapeutic, non-toxic dose to use in Specific Aim 2, in which we will study the pharmacokinetics of adventitially delivered sirolimus. We will use this information to determine how long we need to look for toxic effects in a pivotal efficacy and toxicity study, which is the goal of Specific Aim 3. The innovative product that will be developed in this proposal is a combination device/drug therapy that will be broadly applicable to vascular disease. We believe that the significance of this proposal lies in the fact that (a) we are addressing a recalcitrant clinical problem (b) perivascular or adventitial therapy may be used as an adjunct to several common interventional revascularization techniques and (c) therapeutic success in PAD could be rapidly translated to settings such as coronary and renal artery restenosis or restenosis following coronary and peripheral bypass grafting. If these initial pilot studies are successful, we intend to move into clinical trials and ultimately seek FDA approval for a novel combination product. PUBLIC HEALTH RELEVANCE: The changing demographics of Western societies include an aging population with a near epidemic of obesity, insulin resistance, and diabetes mellitus, causing a dramatic rise in the prevalence of PAD, which impairs the ability to walk and causes pain, nonhealing ulcers and gangrene in the lower extremities. It is a significant public health burden and, at its worst, leads to leg amputations. Among individuals most severely affected, revascularization of the lower extremities to restore circulation is the most effective therapy. However, to date, there has been no effective pharmaceutical strategy to reduce the incidence of restenosis due to intimal hyperplasia in peripheral arteries. Therefore, the relevance of this proposal lies in its potential to improve patency of lower extremity interventions, reduce morbidity, and reduce the significant financial burden currently associated with the treatment of peripheral artery disease (PAD).

描述（由申请人提供）：外周动脉疾病（PAD）影响900万至1200万美国人，每年有150万人需要干预（407,400人接受搭桥或截肢；1,080,000人接受血管成形术、支架或动脉粥样硬化切除术）。不幸的是，只有三分之一的患者在股动脉球囊成形术一年后动脉通畅。裸金属支架[5-7]消除了弹性反冲和限流夹层，但没有显著影响内膜增生引起的再狭窄[3,8 -10]。事实上，放置在股腘段的支架1年的通畅率仅为54-63%，2年的通畅率为28-55%[5,7,11 -12]，药物洗脱支架在消除再狭窄方面并不比裸支架好[13-15]。最近，在外周动脉中使用药物洗脱球囊已显示出改善通畅的潜力，而无需植入支架。基于光的治疗动力学（药物洗脱球囊和支架）将药物的最大浓度置于光壁界面。这明显的缺点是阻碍血管的愈合和再内皮化。最近的数据表明，外膜在内膜增生中起重要作用，有助于新内膜细胞体积和不良重构。我们建议在血管成形术时通过经皮导管将西罗莫司（一种著名的抗再狭窄药物）直接输送到血管外膜，这是一种新型纳米颗粒制剂。这种方法避免了异物植入，并在外膜中产生高浓度，在管腔表面产生较低浓度。墨卡托医疗系统公司开发了一种导管，当气球膨胀时，它可以滑动一根针穿过血管壁，从而可以直接治疗外膜。这种导管的体外输送导致药物在血管周围的圆柱形沉积，形成一个天然的药物洗脱库。在特异性目标1中，我们计划在猪外周动脉再狭窄模型中评估与安慰剂相比，三种不同西罗莫司剂量的影响程度。我们将选择一种治疗性的、无毒的剂量用于特异性Aim 2，我们将研究西罗莫司体外给药的药代动力学。我们将利用这些信息来确定在关键功效和毒性研究中我们需要多长时间来寻找毒性作用，这是Specific Aim 3的目标。在本提案中开发的创新产品是一种广泛适用于血管疾病的联合设备/药物治疗。我们认为，这一建议的意义在于：(a)我们正在解决一个难以解决的临床问题；(b)血管周围或血管外治疗可以作为几种常见介入血运重建技术的辅助手段；(c) PAD治疗的成功可以迅速转化为诸如冠状动脉和肾动脉再狭窄或冠状动脉和外周旁路移植术后再狭窄的情况。如果这些初步的试点研究成功，我们打算进入临床试验，并最终寻求FDA批准一种新的组合产品。