Low-Dose Magneto-Thrombolysis to Expand Stroke Care

低剂量磁溶栓扩大中风治疗范围

• 批准号: 10693650
• 负责人: Francis Milton Creighton
• 金额: $ 152.38万
• 依托单位: UNANDUP, LLC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10693650
• 关键词: 3D Print; Acceleration; Acute; Alteplase; Ambulances; American; Animal Model; Animals; Anterior; Biodistribution; Biological; Biological Assay; Blood; Blood coagulation; Blood flow; Brain; Caring; Cause of Death; Cessation of life; Circulation; Coagulation Process; Custom; Cyclic GMP; Cytolysis; Data Set; Deterioration; Development; Diagnosis; Diffusion; Dose; Drug Kinetics; Economic Burden; Eligibility Determination; Embolism; Ensure; FDA approved; Family suidae; Fibrinogen; Fibrinolytic Agents; Goals; Half-Life; Hemorrhage; Hospitals; Hour; Human; In Vitro; Infusion procedures; Iron; Ischemic Stroke; Knowledge; Location; Magnetic nanoparticles; Magnetism; Marketing; Measures; Mechanics; Metabolism; Methods; Modeling; Morphology; Neurologic; Neurological outcome; Organ; Palliative Care; Pathway interactions; Patient Transfer; Patients; Performance; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Plasma; Procedures; Process; Publishing; Rattus; Reaction; Reperfusion Therapy; Resolution; Risk; Rodent; Safety; Sex Distribution; Silicon Dioxide; Speed; Stroke; Surface; System; Techniques; Technology; Thrombectomy; Time; Underserved Population; United States; absorption; biomaterial compatibility; cost; disability; efficacy study; hemodynamics; improved; in vivo; invention; iron oxide; meetings; millimeter; nanoparticle; novel; portability; prevent; programs; prototype; response; safety assessment; safety study; standard of care; stroke event; stroke intervention; stroke outcome; stroke therapy; stroke victims; success; thrombolysis; tool

Acute ischemic stroke (AIS) results from a blood clot in the neurovasculature and is a leading cause of death and 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 AIS therapies include FDA-approved thrombolysis using alteplase (i.e., tissue plasminogen activator, tPA) 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 modest ~15% improvement in stroke outcomes, resulting in only ~10% fully recovering. However, due to alteplase's ~7% dose-dependent hemorrhage risk, thrombolysis remains contraindicated for mild and wake-up strokes which together make up ~60% of all AIS events. Currently, thrombolysis usage within the US remains low (~10%) with 90% of all AIS victims only receiving palliative care. Thus, there is an urgent need to improve the efficacy and safety of thrombolysis and extend thrombolysis to more AIS victims. UNandUP has invented a novel nanoparticle-based thrombolysis platform to safely accelerate alteplase to AIS-associated blood clots, thereby overcoming restrictive hemodynamics known to prevent alteplase from reaching the occlusion. The platform overcomes this barrier by 1) conveying alteplase-conjugated magnetic nanoparticles to the clot’s surface more than 350X faster than normal biological diffusion (so that lysis starts within minutes versus hours), and 2) mechanically mixing alteplase at the clot’s surface to improve lysis using an alteplase dose nearly 250X lower than currently approved (which promises to eliminate alteplase’s elevated hemorrhage risk). C3i participation and FDA/regulatory meetings confirm a likely CDER pathway which, although lengthier and more costly than a CDRH pathway, results in a commercially attractive pharmaceutical product. The platform is affordable to hospitals, does not require precise knowledge of the clot’s location, and is intended to support EMT transfers between spoke and hub stroke centers, thereby ensuring thrombectomy is not delayed. Once proven safe and effective, UNandUP’s goal is to extend the benefits of thrombolysis to nearly all 700,000 AIS victims, which is 10X more than currently treated. By leveraging UNandUP’s prior success in developing magnetic nanoparticles and portable magnet systems, the aims of this effort can focus on synthesizing cGMP nanoparticles using proprietary magnetic cores and conducting safety and efficacy studies in support of an FDA-CDER regulatory approval process.

急性缺血性中风 (AIS) 由神经血管系统中的血凝块引起，是导致死亡的主要原因 在美国，AIS 每年影响超过 700,000 名美国人。 到 2030 年，预计 AIS 的经济负担将超过 65%。 仅在美国就花费了 180B 美元。 标准 AIS 疗法包括 FDA 批准的使用阿替普酶（即组织纤溶酶原）的溶栓治疗 中风发作后 4.5 小时内注射激活剂（tPA），并尽早进行血栓切除术以治疗大血管闭塞 （最长 24 小时）与血栓切除术不同，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，因此溶栓仍然是治疗血栓栓塞的重要一线工具。 治疗诊断为 AIS 的患者时，溶栓治疗可带来约 15% 的适度改善。 然而，由于阿替普酶的剂量依赖性，约 7% 的患者完全康复。 出血风险，溶栓治疗对于轻度中风和清醒中风仍然是禁忌，这两者共同构成 目前，美国境内约 60% 的 AIS 事件中溶栓治疗的使用率仍然较低（约 10%），占所有 AIS 事件的 90%。 因此，迫切需要提高姑息治疗的有效性和安全性。 溶栓治疗并将溶栓治疗范围扩大到更多 AIS 患者。 UNandUP 发明了一种新型纳米颗粒溶栓平台，可安全加速阿替普酶 AIS 相关的血栓，从而克服已知可防止阿替普酶的限制性血流动力学 该平台通过 1) 传输阿替普酶共轭磁性克服了这一障碍。 纳米颗粒到达凝块表面的速度比正常生物扩散快 350 倍（因此裂解开始 在几分钟内而不是几小时内），以及2）在凝块表面机械混合阿替普酶以改善溶解 阿替普酶剂量比目前批准的剂量低近 250 倍（这有望消除阿替普酶升高的副作用） C3i 的参与和 FDA/监管会议确认了可能的 CDER 途径，其中， 尽管比 CDRH 途径更长且成本更高，但仍可产生具有商业吸引力的药物 该平台对于医院来说是负担得起的，不需要精确了解血栓的位置，并且 旨在支持轮辐中心和轮毂卒中中心之间的 EMT 转移，从而确保血栓切除术 一旦被证明是安全有效的，UNandUP 的目标是将溶栓的益处扩大到 几乎所有 700,000 名 AIS 受害者，比目前接受治疗的人数多了 10 倍。 在开发磁性纳米颗粒和便携式磁体系统方面取得成功，这项工作的目标可以集中在 使用专有磁芯合成 cGMP 纳米颗粒并进行安全性和有效性 支持 FDA-CDER 监管审批流程的研究。