ProHealing Drug Alternative for Coronary Drug Eluting Stents

描述（由申请人提供）：冠状动脉药物洗脱支架的ProHealing药物替代品我们的目标是通过在药物洗脱支架（DES）中加入生长因子活性调节剂PRM-100，开发一种治疗冠状动脉疾病的新型、更安全、更有效的方法。当前DES具有抗肿瘤作用（即细胞抑制或细胞毒性） 阻止平滑肌细胞（SMC）扩张从而预防再狭窄的药物。然而，由于抗肿瘤药物多年来要么杀死支架部位的内皮细胞，要么使其功能障碍，患者面临的再狭窄概率随着时间的推移而增加，并且易于发生危及生命的血栓形成事件（例如致命性血栓），这是一种需要长期或无限期给予强效双重抗血小板治疗（DAPT）的副作用。值得注意的是，许多患者不依从DAPT治疗方案;此外，那些依从DAPT的患者会产生显著的不良反应（例如，6%的大出血和11%的轻微出血并发症）。为了避免这些并发症，我们建议用PRM-100代替抗肿瘤药物，PRM-100通过下调和调节生长因子活性，有效抑制平滑肌细胞的生长和增殖，同时保持对内皮细胞无毒。在支架植入部位重建完整的功能性内皮提供了一个天然的抗血栓形成表面，可主动控制动脉壁重塑，以限制再狭窄。我们的假设是，我们可以找到PRM-100的最佳治疗剂量，并将其与涂层一起有效地应用于从DES局部递送到冠状动脉中， 性能优于当前DES。为了验证这一假设，我们提出了以下具体目标：目标1。细胞培养研究：平滑肌细胞抑制和对内皮细胞的影响 PRM-100里程碑：证明PRM-100在低且可实现的剂量和浓度下有效地抑制SMC增殖，同时对内皮细胞也是无毒的[例如，5 - 30 μ g/ml，洗脱长达30天]。PRM-100将与目前用于DES的药物进行比较，特别是西罗莫司或西罗莫司类似物，如依维莫司。目标二。使用DES平台的体内疗效。里程碑与当前技术相比，通过与仅含聚合物的DES直接比较，以及与裸金属支架和其他DES间接比较，PRM-100洗脱支架的内膜增生减少、再内皮化改善和无炎症来测量治疗特征改善。 成功完成I期SBIR后，我们将对PRM-100用于治疗冠状动脉疾病的药物洗脱支架进行概念验证，并准备启动II期SBIR，其中将包括深入的药代动力学/动力学，可能是完全生物可吸收的支架，GLP动物研究和首次人体试验的准备。 公共卫生相关性：我们的目标是通过在药物洗脱支架（DES）中加入不同类型的药物PRM-100，开发一种治疗冠状动脉疾病的新方法。为了避免目前在DES中使用的细胞损伤或细胞杀伤药物的并发症，我们建议在细胞培养物和模拟支架的金属圆盘以及动物研究中的支架上测试PRM- 100，其抑制平滑肌细胞的生长和增殖，同时保持对内皮细胞无毒。在成功完成第一阶段SBIR后，我们将对在DES中使用PRM- 100治疗冠状动脉疾病进行概念验证，并准备启动第二阶段SBIR，这将使我们能够为临床试验做好准备。

DESCRIPTION (provided by applicant): ProHealing Drug Alternative for Coronary Drug Eluting Stents Our goal is to develop a novel, safer and more efficacious approach for treating Coronary Artery Disease, by incorporating a modulator of growth factor activity, PRM-100, within a Drug Eluting Stent (DES). Current DES elute anti-neoplastic (i.e. cytostatic or cytotoxic) agents to block the expansion of smooth muscle cells (SMC) and thereby prevent restenosis. However, as anti-neoplastics either kill or render endothelial cells at the stent site dysfunctiona for many years, patients face an increasing probability of restenosis with time and are predisposed toward life-threatening thrombotic events (e.g. fatal clots), a side effect that necessitates chronic or indefinite administration of potent Dual Anti-Platelet Therapies (DAPT). Notably, many patients are non-compliant with the DAPT treatment regime; furthermore, those that do comply with DAPT incur significant adverse effects (e.g. 6% major bleeding and 11% minor bleeding complications). To avoid these complications, we propose to replace anti-neoplastics with PRM-100, which works by down-regulating and modulation of growth factor activity, effectively inhibiting growth and proliferation of smooth muscle cells, while remaining non-toxic to endothelial cells. Reestablishment of an intact functional endothelium at the stented site provides a natural anti-thrombotic surface that actively controls arterial wall remodeling to limit restenosis. Our hypothesis is that we can find an optimal therapeutic dose of PRM-100 and effectively apply it with a coating for local delivery from a DES into a coronary artery which will perform better than current DES. To test this hypothesis, we propose the following specific aims: Aim 1. Cell culture studies: Inhibition of smooth muscle cell and effect on endothelial cells by PRM-100. Milestone: Demonstration that PRM-100 effectively inhibits SMC proliferation while also being non-toxic to endothelial cells at a low and achievable dose and concentration [e.g., 5 - 30 ¿g per ml, eluted for up to a 30 day period]. PRM-100 will be compared to drugs currently used on DES, specifically, sirolimus or a sirolimus analogue such as everolimus. Aim 2. In vivo efficacy using a DES platform. Milestone. Improved therapeutic profile as compared to current technology as measured by decreased intimal hyperplasia, improved re-endothelialization, and absence of inflammation in PRM-100-eluting stents compared directly to polymer-only DES, but also indirectly to bare metal stents and other DES. On successful completion of this Phase I SBIR, we will have proof-of-concept for the use of PRM-100 in a drug eluting stent for the treatment of coronary artery disease, and be poised to launch a Phase II SBIR, which will include in-depth pharmacokinetics/dynamics, potentially a fully bioabsorbable stent, GLP Animal Studies and preparation for First-in-Man. PUBLIC HEALTH RELEVANCE: Our goal is to develop a novel approach for treating coronary artery disease, by incorporating a different class of drug, PRM-100, within a Drug Eluting Stent (DES). To avoid the complications that currently occur from the use of the cell-damaging or cell-killing drugs now used in DES, we propose to test PRM- 100, which inhibits growth and proliferation of smooth muscle cells, while remaining non-toxic to endothelial cells, in cell cultue and on metal discs that simulate a stent and also on stents in animal studies. On successful completion of this Phase I SBIR, we will have proof-of-concept for the use of PRM- 100 in a DES for the treatment of coronary artery disease, and be poised to launch a Phase II SBIR, which will allow us to prepare for clinical testing.