Improved Adventitial Sirolimus Therapy for Peripheral Artery Restenosis

描述(申请人提供)：外周动脉疾病(PAD)每年影响900万至1200万美国人[1]，150万人需要干预(407400人接受搭桥或截肢；1080000人接受血管成形术、支架或动脉粥样硬化切除术)[3]。不幸的是，在股动脉球囊血管成形术一年后，只有三分之一的患者有动脉未闭[4]。裸金属支架[5-7]消除了弹性回弹和限流性夹层，但对因内膜增生引起的再狭窄没有明显影响[3，8-10]。事实上，放置在股静脉段的支架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的效果并不比裸支架好[13-15]。最近，在外周动脉中使用药物洗脱球囊已经显示出在不需要植入支架的情况下改善通畅性的潜力[16]。基于管腔的治疗(药物洗脱球囊和支架)的动力学将药物的最大浓度放置在管腔-壁界面处。这有一个明显的缺点，即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，导致新生内膜细胞体积增加和不良重塑。我们建议在血管成形术时通过经皮导管将西罗莫司直接输送到血管外膜，西罗莫司是一种新型纳米制剂，是一种著名的抗再狭窄药物。这种方法避免了异物植入，并在外膜产生高浓度，在管腔表面产生低浓度。墨卡托医疗系统公司开发了一种导管，当气球充气时，只需一根针就能穿过血管壁，从而使治疗直接进入血管外膜。这种导管的外膜给药导致药物在血管周围的圆柱状沉积，形成一个天然的药物洗脱储存库。在具体目标1中，我们计划评估三种不同剂量的西罗莫司与安慰剂在猪外周动脉再狭窄模型中的作用程度。我们将选择一种治疗性的、无毒的剂量用于特定的目标2，在该剂量中我们将研究外周给药的西罗莫司的药代动力学。我们将利用这些信息来确定我们需要在关键的疗效和毒性研究中寻找毒性效应的时间，这是特定目标3的目标。在这项提案中开发的创新产品是一种将广泛适用于血管疾病的设备/药物联合疗法。我们认为，这项建议的意义在于：(A)我们正在解决顽固性的临床问题；(B)血管周围或外膜治疗可以作为几种常见的介入性血管重建术的辅助手段；(C)PAD的治疗成功可以迅速转化为冠状动脉和肾动脉再狭窄或冠状动脉和外周搭桥术后的再狭窄。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。 与公共健康相关：西方社会不断变化的人口结构包括老龄化的人口，肥胖、胰岛素抵抗和糖尿病几乎流行，导致PAD患病率急剧上升，PAD损害行走能力，并导致疼痛、无法愈合的溃疡和下肢坏疽。这是一个重大的公共卫生负担，在最糟糕的情况下，会导致腿部截肢。在受影响最严重的个体中，下肢血运重建以恢复循环是最有效的治疗方法。然而，到目前为止，还没有有效的药物策略来减少由于外周动脉内膜增生而导致的再狭窄的发生率。因此，这项建议的相关性在于它有可能改善下肢介入治疗的通畅性，减少发病率，并减轻目前与外周动脉疾病(PAD)治疗相关的重大经济负担。

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).