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）是由神经血管内的血块引起的，是死亡的主要原因 和美国的神经残疾（美国）。 AIS每年影响超过70万美国人 死亡或严重残疾的机会为65％。到2030年，预计AIS经济燃烧将超过 仅在美国，$ 180B。 标准AIS疗法包括使用拟层层酶（即组织纤溶酶原）进行FDA批准的溶栓分解 激活剂，TPA）在中风发作的4.5小时内，最早可用于大容器闭塞的血栓切除术 （到24小时）。与血栓切除术相反，溶栓不需要确认血管阻塞。 由于只有约10％的AIS恐怖受害者有资格进行血栓切除术，因此溶栓仍然是关键的第一行工具 治疗被诊断为AIS的人。使用时，溶栓分解与适度的改善相关 在中风结果中，只能完全恢复约10％。但是，由于交替的约7％剂量依赖性 出血风险，溶栓仍然是禁忌的，与轻度和唤醒中风一起弥补 所有AIS事件中的60％。目前，美国境内的溶栓使用量仍然很低（约10％），而所有AIS的90％ 只需接受姑息治疗。那迫切需要提高 溶栓并将溶栓延伸到更多的AIS恐怖受害者。 UnAndup发明了一个新型的基于纳米颗粒的溶栓平台，以安全地加速替代方案 与AIS相关的血凝块，从 达到阻塞。该平台克服了这一障碍，通过1）输送高速叠酶偶联的磁性 纳米粒子到凝块表面的表面比正常生物扩散快350倍以上（以便裂解开始 在几分钟之内与小时内），以及2）在凝块表面机械混合高度叠层，以改善使用的裂解 替代剂量比当前批准的近250倍（有望消除Alterse升高 出血风险）。 C3I参与和FDA/监管会议证实了可能的CDER途径， 虽然比CDRH途径更长，更昂贵，但导致商业上有吸引力的药物 产品。该平台对医院负担得起，不需要精确了解凝块的位置，并且 旨在支持辐条和轮毂卒中中心之间的EMT转移，从而确保血栓切除术 没有延迟。一旦被证明是安全有效的，UnAndup的目标是将溶栓的好处扩展到 几乎所有700,000 AIS可怕，比目前处理的多10倍。通过利用UnAndup的先验 在开发磁性纳米颗粒和便携式磁铁系统方面的成功，这项工作的目的可以集中 使用专有磁芯合成CGMP纳米颗粒并进行安全性和效率 支持FDA-CDER监管批准过程的研究。