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

急性缺血性中风（AIS）是脑动脉中的血块的结果。目前，AIS仍是领先的 这是一个杀手，也是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，再灌注时间对于预防死亡和改善神经功能至关重要。 结果。虽然在美国（US）与缺血性卒中相关的经济负担很高，但 预计将从2013年的720亿美元增加到2030年的1830亿美元。 静脉使用组织纤溶酶原激活剂（tPA）是AIS的标准治疗，伴血栓切除术 推荐用于前循环中的近端大血管闭塞。这一战略导致 与单独使用tPA相比，长期神经学结局得到改善。然而，超过一半的血栓切除术治疗 患者死亡或留下中度至重度残疾，尽管大多数实现完全或部分- 完全恢复血流。血栓切除术后无法触及远端栓子是不良的主要原因 结果，这导致多达一半的情况下不完全流动。未实现完全再通的患者 倾向于住院时间更长，神经功能改善较弱，长期神经功能恶化 与完全再通的患者相比，结局更差，出血更多。当前没有选项 目前的工具太大并且动脉内输注溶血栓剂 由于远端闭塞在近端产生停滞的血柱， 限制它们的扩散速度在每小时几毫米以内。 Pulse Therapeutics，Inc. (PTI)已经取得了突破性的发现， 输送溶栓剂的速度提高100倍以上。体外和体内研究证实，该技术提高了 血栓溶解剂输送和凝块溶解。还表明，低剂量的替奈普酶（TNK） 上级于tPA。该项目的目标是开发动脉内手术的技术， AIS的治疗对于I期，将进行实验室、体外和体内工作，以证明 概念和优化TNK和粒子剂量和治疗输送。FDA使用I期结果的反馈将 努力实现第二阶段目标。第二阶段将评估该系统对TNK药代动力学的影响， 出血加重。此外，将开发一个血管造影套件兼容工作站， 将在荧光透视下重复使用神经体模的血流研究，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具有说服力的设备进行评估， 作用方式和生物相容性初步研究。重要的是，PTI技术支持FDA的 使命是加强综合性卒中中心的价值，并承诺改善对近 35万例AIS患者的前循环中出现可见血块。如果成功，这项技术将 代表了第一个药物输送纳米技术批准作为医疗设备在美国。

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.