Improved Adventitial Rapamycin 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涂层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]。然而，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-壁界面处。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关键作用，有助于新生内膜细胞体积和不良重塑。我们已经成功地完成了1期研究的目标，并且在临床前研究中，我们已经证明了无毒的有效剂量的雷帕霉素，一种新型纳米颗粒制剂中的众所周知的抗再狭窄剂，在血管成形术时通过经皮导管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。该导管已用于人体初步研究，成功的外膜输送导致药物在血管周围圆柱形沉积，形成天然药物洗脱储库。我们现在建议将这项研究推进到人体临床试验中，具体目的是确认安全性，同时证明在外周动脉血管成形术时将雷帕霉素递送到外膜的积极生物学效应和临床益处。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2期研究成功，我们打算进入关键的临床试验，并最终寻求FDA批准一种新的组合产品。

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 bu 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-coated balloons in the peripheral artery has shown potential to improve patency without the need to implant stents [16]. However, 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 a critical role in intimal hyperplasia, contributing to both neointimal cell volum and adverse remodeling. We have successfully completed the aims of Phase 1 research and in pre-clinical studies we have demonstrated non-toxic, efficacious doses of rapamycin, a well-known anti-restenotic agent in a novel nanoparticle formulation, delivered 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. The catheter has been used in human pilot studies with successful adventitial delivery leading to cylindrical deposition of drugs around the vessel, creating a natural drug-eluting reservoir. We are now proposing to advance this research into human clinical trials, with Specific Aims of confirming safety while demonstrating the positive biological effect and clinical benefits of rapamycin delivered to the adventitia at the time of peripheral artery angioplasty. 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 Phase 2 studies are successful, we intend to move into pivotal clinical trials and ultimately seek FDA approval for a novel combination product.