Magnetically Enhanced Diffusion for Intra-Arterial Treatment of Acute Ischemic Stroke

急性缺血性中风(AIS)是脑动脉内血栓形成的结果。目前，AIS仍然是领先的 杀手和长期残疾的主要原因，每年影响近70万美国人。因为 脑组织迅速死亡，再灌注时间对防止死亡和改善神经功能至关重要 结果。虽然在美国，与缺血性中风相关的经济负担很高，但 预计从2013年的70亿美元增加到2030年的1,830亿美元。 静脉使用组织纤溶酶原激活剂(TPA)是AIS的标准护理，并进行血栓切除术 推荐用于前循环近端大血管闭塞。这一战略导致了 与单独使用tPA相比，长期神经结果的改善。然而，超过一半的血栓切除治疗 患者死亡或留下中到重度残疾，尽管大多数人实现了完全或部分- 血流量完全恢复。血栓摘除后无法接近的远端栓子是不良的主要原因 结果，在多达一半的案例中导致不完整的流动。未实现完全再通的患者 往往住院时间更长，表现出较弱的神经改善，长期神经状况较差 结果，与完全再通的患者相比，发生更多的出血。当前没有选项 存在用于治疗远端血栓的方法，因为目前的工具太大且动脉内注入溶栓剂 药物显示，由于远端闭塞造成近端血柱停滞，治疗效果有限甚至没有成功。 凝块将它们的扩散限制在每小时不到几毫米。 脉冲治疗公司(PTI)已经取得了一项突破性发现，使用磁性粒子来辅助 输送溶栓剂的速度提高100倍以上。体外和体内研究证实，这项技术改进了 溶栓剂输送和血栓溶解。研究还表明，低剂量的替替普酶(TNK)可以 优于tPA。该项目的目标是开发用于动脉内手术的技术 AIS的治疗。对于第一阶段，将进行体外和体内的台式工作，以证明 概念和优化秋水仙素和颗粒剂量和治疗提供。FDA将使用第一阶段结果进行反馈 寻求改进第二阶段的目标。第二阶段将评估该系统对秋明大学药代动力学的影响 出血加重。此外，还将开发一个与血管成像套件兼容的工作站，并 使用神经模型的血流研究将在透视下重复进行，以评估预期的临床工作流程。 FDA的早期参与表明，该技术可以作为一种有说服力的设备进行评估 作用方式和生物相容性的初步研究。重要的是，PTI技术支持FDA的 使命是加强综合性中风中心的价值，并承诺改善对近 350,000名AIS患者前循环可见凝块。如果成功，这项技术将 代表了第一个在美国被批准作为医疗设备的药物输送纳米技术。

Acute ischemic stroke (AIS) is the result of a blood clot in a cerebral artery. Currently, AIS remains a leading killer and the leading cause of long-term disability, which annually impacts nearly 700,000 Americans. Because brain tissue rapidly dies, time to reperfusion is critical in both preventing death and improving neurological outcomes. While economic burden associated with ischemic stroke are high in the United States (US), it is projected to increase from $72B in 2013 to $183B by 2030. Intravenous use of tissue plasminogen activator (tPA) is the standard of care for AIS, with thrombectomy recommended for proximal large vessel occlusion in the anterior circulation. This strategy results in improvements in long-term neurological outcomes over tPA alone. However, over half of thrombectomy-treated patients die or are left moderately-to-severely disabled, despite a majority achieving complete or partially- complete blood flow restoration. Inaccessible distal emboli post thrombectomy are a primary reason for poor outcomes, which result in incomplete flow in up to half of cases. Patients not achieving complete recanalization tend to be hospitalized longer, show weaker neurological improvements, have worse long-term neurological outcomes, and experience more hemorrhage, versus those with complete recanalization. No options currently exist for treating distal emboli given that current tools are too large and intra-arterial infusion of thrombolytic agents has shown limited-to-no success due to distal occlusions creating stagnant columns of blood proximal to the clot which restricts their diffusion to less than a few millimeters per hour. Pulse Therapeutics, Inc. (PTI) has made a breakthrough discovery using magnetic particles to adjunctively convey thrombolytic agents over 100X faster. In vitro and in vivo work confirm that this technology improves thrombolytic agent conveyance and clot lysis. It has also been shown that low doses of tenecteplase (TNK) are superior to tPA. This project’s aims are to develop the technology for an intra-arterial procedure in the treatment of AIS. For Phase I, benchtop, in vitro, and in vivo work will be conducted to demonstrate proof of concept and optimize TNK and particle dosing and therapy delivery. FDA feedback using Phase I results will be sought to improve Phase II aims. Phase II will assess the system’s impact on TNK pharmacokinetics and aggravation of hemorrhage. In addition, an angiography suite-compatible workstation will be developed and flow studies using neuro phantoms will be repeated under fluoroscopy to assess anticipated clinical workflow. Early FDA engagement indicates that the technology may be evaluated as a device given persuasive mode of action and biocompatibility preliminary studies. Importantly, the PTI technology supports the FDA’s mission to reinforce the value of comprehensive stroke centers and promises to improve care for the nearly 350,000 AIS victims showing visible clot in the anterior circulation. If successful, this technology would represent the first drug delivery nanotechnology approved as a medical device in the US.