Improved Adventitial Sirolimus Therapy for Peripheral Artery Restenosis

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[1]，每年将有150万人需要干预（407，400人接受旁路或截肢; 1，080，000人接受血管成形术、支架或斑块切除术）[3]。不幸的是，只有三分之一的患者在股动脉球囊血管成形术后一年动脉通畅[4]。裸金属支架[5-7]消除了弹性回缩和限流夹层，但未显著影响内膜增生引起的再狭窄[3，8-10]。事实上，放置在股腘动脉段的支架在1年时的通畅率仅为54-63%，在2年时为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显示出在无需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置于管腔-壁界面。这具有阻碍血管愈合和再内皮化的明显缺点。最近的数据表明，外膜在内膜增生中起着重要作用，有助于新生内膜细胞体积和不良重塑。我们建议在血管成形术时通过经皮导管将西罗莫司（一种新型纳米颗粒制剂中的众所周知的抗再狭窄剂）直接递送到血管外膜中。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。Mercator MedSystems开发了一种导管，当球囊膨胀时，该导管可将单针滑动穿过血管壁，从而允许直接进入外膜进行治疗。使用该导管的外膜递送导致药物在血管周围的圆柱形沉积，形成天然药物洗脱储库。在具体目标1中，我们计划在猪外周动脉再狭窄模型中评估三种不同西罗莫司剂量与安慰剂相比的作用程度。我们将选择一种治疗、无毒剂量用于特定目标2，其中我们将研究外膜给药西罗莫司的药代动力学。我们将使用这些信息来确定我们需要多长时间来寻找关键疗效和毒性研究中的毒性作用，这是具体目标3的目标。本提案中将开发的创新产品是一种广泛适用于血管疾病的组合器械/药物治疗。我们认为，该建议的重要性在于：（a）我们正在解决一个棘手的临床问题（B）血管周围或外膜治疗可用作几种常见介入血运重建技术的辅助治疗，（c）PAD的治疗成功可迅速转化为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等情况。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。 公共卫生相关性：西方社会不断变化的人口统计学特征包括人口老龄化，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下肢疼痛、不愈合溃疡和坏疽。这是一个重大的公共卫生负担，在最坏的情况下，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，迄今为止，还没有有效的药物策略来降低由于外周动脉内膜增生引起的再狭窄的发生率。因此，该提案的相关性在于其改善下肢介入术通畅性、降低发病率和减少目前与外周动脉疾病（PAD）治疗相关的重大经济负担的潜力。

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).