ProHealing Drug Alternative for Coronary Drug Eluting Stents

描述(申请人提供)：冠状动脉药物洗脱支架的ProHeating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的、更安全和更有效的方法。目前的DES洗脱抗肿瘤(即细胞抑制或细胞毒性) 药物可以阻止平滑肌细胞(SMC)的扩张，从而防止再狭窄。然而，随着抗肿瘤药物杀死或使支架部位的内皮细胞功能障碍多年，患者面临着随着时间的推移再狭窄的可能性增加，并容易发生危及生命的血栓事件(例如致命血栓)，这一副作用需要长期或无限期地实施有效的双重抗血小板疗法(DAPT)。值得注意的是，许多患者不遵守DAPT治疗方案；此外，那些确实遵守DAPT治疗方案的患者会产生严重的不良反应(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取代抗肿瘤药物，PRM-100通过下调和调节生长因子活性，有效地抑制平滑肌细胞的生长和增殖，同时保持对内皮细胞的无毒性。在支架植入部位重建完整的功能性内皮细胞提供了一个天然的抗血栓表面，该表面积极控制动脉壁重构，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，并有效地将其与涂层一起从DES局部输送到冠状动脉，这将 性能比当前的DES更好。为了验证这一假说，我们提出了以下具体目标：目的1.细胞培养研究：抑制平滑肌细胞和对内皮细胞的影响 由PRM-100提供。里程碑：证明PRM-100在低和可实现的剂量和浓度(例如，每毫升5-30？克，洗脱时间长达30天)下有效抑制SMC增殖，同时对内皮细胞无毒。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，如埃维洛莫斯。目的2.使用DES平台的体内疗效。这是一个里程碑。与目前的技术相比，PRM-100洗脱支架的治疗效果有所改善，表现为减少了内膜增生，改善了再内皮化，并且没有炎症，与仅使用聚合物的DES相比，也间接与裸金属支架和其他DES相比。在成功完成这一第一阶段SBIR后，我们将拥有将PRM-100用于治疗冠状动脉疾病的药物洗脱支架的概念验证，并准备推出第二阶段SBIR，其中将包括深入的药代动力学/动力学、潜在的完全生物吸收支架、GLP动物研究和第一人的准备。 公共卫生相关性：我们的目标是开发一种治疗冠状动脉疾病的新方法，通过在药物洗脱支架(DES)中加入一种不同类别的药物PRM-100。为了避免目前使用DES中使用的破坏细胞或杀死细胞的药物而出现的并发症，我们建议在细胞培养和模拟支架的金属圆盘上以及动物研究中的支架上测试PRM-100，它可以抑制平滑肌细胞的生长和增殖，同时对内皮细胞保持无毒。在第一阶段SBIR成功完成后，我们将对PRM-100在DES中用于治疗冠状动脉疾病进行概念验证，并准备推出第二阶段SBIR，这将使我们能够为临床测试做准备。

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.