Flow Acceleration for Stroke Thrombolysis (FAST) System

中风溶栓 (FAST) 系统的流量加速

• 批准号: 10253434
• 负责人: Francis Milton Creighton
• 金额: $ 121.18万
• 依托单位: UNANDUP, LLC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-15 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10253434
• 关键词: Acceleration; Acute; Address; Alteplase; American; Anterior; Biological; Blood Circulation; Blood coagulation; Cause of Death; Cessation of life; Coagulation Process; Cytolysis; Data; Diagnosis; Diffusion; Dose; Economic Burden; FDA approved; Feasibility Studies; Fibrinolytic Agents; Hemorrhage; Hospitals; Hour; Infusion procedures; Iron; Ischemic Stroke; Label; Magnetism; Mechanics; Nature; Neurologic; Palliative Care; Pathway interactions; Patient Transfer; Process; Recovery; Risk; Safety; Silicon Dioxide; Stroke; Surface; System; Technology; Thrombectomy; Time; Travel; Underserved Population; United States; acute care; disability; hemodynamics; improved; in vivo; meetings; nanoparticle; nanoparticle delivery; novel; prevent; standard of care; stroke event; stroke outcome; stroke patient; stroke therapy; stroke victims; thrombolysis; tool

Acute ischemic stroke (AIS) results from a blood clot in the neurovasculature and is the 5th leading cause of death and 1st leading cause of neurological disability in the United States (US). AIS impacts more than 700,000 Americans annually, with a 65% chance of death or severe disability. By 2030, it is expected that the AIS economic burden will exceed $180B in the US alone. Standard of care AIS therapies include the use of the FDA approved thrombolytic agent alteplase (i.e., tissue plasminogen activator) within 4.5 hours of stroke onset and earliest-possible thrombectomy for large vessel occlusions (out to 24hrs). In contrast to thrombectomy, thrombolysis does not require confirmation of a vessel occlusion. Because only ~10% of AIS victims are eligible for thrombectomy, thrombolysis remains a critical first line tool to treat those diagnosed with AIS. When employed, thrombolysis is associated with a ~15% improvement in stroke outcomes with ~10% fully recovering. However, due to the ~7% dose-dependent associated hemorrhage rate of alteplase, thrombolysis is contraindicated for mild and wake-up strokes which together make up ~60% of all AIS events. Due to safety concerns and limited reliability, usage of thrombolysis in the US remains low (~10%) with 90% of all AIS victims receiving only palliative care. There remains an urgent need to improve first line use of thrombolysis which can be expanded to all AIS victims. UNandUP has invented a novel thrombolysis platform to safely accelerate alteplase to the obstructing blood clot, thereby overcoming the restrictive hemodynamics known to prevent alteplase from quickly reaching the occlusion. The proposed magnetic infusion platform overcomes this barrier by 1) adjunctively conveying alteplase to the clot’s surface more than 100X faster than normal biological diffusion (i.e., minutes vs. hours), and 2) mechanically mixing alteplase at the clot’s surface so that lysis is more reliable. Because alteplase is not conjugated and the mode of action is purely mechanical in nature, FDA meetings confirmed a CDRH IDE pathway is appropriate in support of an FDA Early Feasibility Study, which is a shorter and less expensive pathway compared to a CDER IND process. Importantly, the technology is affordable, does not require precise focusing, and can be configured to travel with patients transferred between hospitals for thrombectomy. Once proven safe and effective using current FDA approved alteplase labeling, UNandUP intends to expand thrombolysis to mild and wake up strokes by increasing the lysis efficacy of smaller alteplase doses known not to induce hemorrhage. If successful, thrombolysis could be safely extended to all 700,000 AIS victims for the first time, which is 10X more than currently treated. The project’s aims include 1) building the magnetic infusion subcomponents (magnetic workstation, silica coated iron nanoparticles, nanoparticle delivery system), and conducting 2) mechanism of action, 3) in vivo safety, and 4) clot interaction studies. Data obtained for the proposed effort will be critical to address FDA concerns in advance of an FDA Early Feasibility Study IDE.

急性缺血性中风 (AIS) 由神经血管系统中的血凝块引起，是导致脑卒中的第五大原因 美国 (US) 的死亡和神经功能障碍的第一大原因。 AIS 影响超过 700,000 美国人每年有 65% 的机会死亡或严重残疾。到 2030 年，预计 AIS 仅在美国，经济负担就将超过 $180B。 标准护理 AIS 疗法包括使用 FDA 批准的溶栓剂阿替普酶（即 组织纤溶酶原激活剂）在中风发作后 4.5 小时内进行，并且对于大的患者应尽早进行血栓切除术 血管闭塞（24 小时内）。与血栓切除术相比，溶栓不需要确认 血管闭塞。由于只有约 10% 的 AIS 受害者有资格接受血栓切除术，因此溶栓治疗仍然是一种 治疗 AIS 患者的重要一线工具。当使用时，溶栓与 中风结果改善约 15%，完全恢复约 10%。然而，由于约 7% 的剂量依赖性 与阿替普酶相关的出血率，溶栓治疗对于轻度和觉醒中风是禁忌的。 合计约占所有 AIS 事件的 60%。出于安全考虑和有限的可靠性，溶栓的使用 在美国，这一比例仍然很低（约 10%），90% 的 AIS 受害者仅接受姑息治疗。仍然存在一个 迫切需要改进溶栓的一线使用，并将其扩大到所有 AIS 受害者。 UNandUP 发明了一种新型溶栓平台，可安全加速阿替普酶到达阻塞部位 血凝块，从而克服已知阻止阿替普酶快速到达的限制性血流动力学 闭塞。所提出的磁力输注平台通过 1) 辅助输送克服了这一障碍 阿替普酶到达凝块表面的速度比正常生物扩散快 100 倍以上（即几分钟与几小时）， 2) 在凝块表面机械混合阿替普酶，使裂解更加可靠。因为阿替普酶是 未结合且作用模式本质上是纯机械的，FDA 会议确认了 CDRH IDE 途径适合支持 FDA 早期可行性研究，该研究时间更短且成本更低 途径与 CDER IND 流程相比。重要的是，该技术价格实惠，不需要精确 聚焦，并且可以配置为与在医院之间转移进行血栓切除术的患者一起旅行。一次 使用当前 FDA 批准的阿替普酶标签证明安全有效，UNandUP 打算扩大 通过增加已知未知剂量的较小阿替普酶的溶解功效，溶栓治疗轻度中风并唤醒中风 以诱发出血。如果成功，溶栓治疗可以安全地扩展到所有 700,000 名 AIS 受害者 第一次，比目前治疗的多 10 倍。该项目的目标包括 1) 构建磁导流 子组件（磁性工作站、二氧化硅涂层铁纳米颗粒、纳米颗粒输送系统），以及 进行 2) 作用机制、3) 体内安全性和 4) 凝块相互作用研究。获得的数据为 拟议的工作对于在 FDA 早期可行性研究 IDE 之前解决 FDA 的担忧至关重要。