Low-Dose Magneto-Thrombolysis to Expand Stroke Care

急性缺血性卒中（AIS）是由神经血管中的血块引起的，是导致死亡的主要原因 和神经系统残疾在美国（US）。AIS每年影响超过70万美国人， 死亡或严重残疾的几率为65%到2030年，预计AIS经济负担将超过 仅在美国就有1800亿美元。 标准AIS疗法包括FDA批准的使用阿替普酶的溶栓（即，组织纤溶酶原 激活剂，tPA），并尽早对大血管闭塞进行血栓切除术 (out至24小时）。与血栓切除术不同，溶栓不需要确认血管闭塞。 因为只有~10%的AIS患者适合血栓切除术，溶栓仍然是治疗AIS的关键一线工具。 治疗被诊断为AIS的患者。当使用时，溶栓与适度~15%的改善相关 在中风的结果，导致只有~10%完全恢复。然而，由于阿替普酶约7%的剂量依赖性， 出血风险，溶栓仍然禁忌轻度和唤醒中风，共同构成 约60%的AIS事件。目前，美国溶栓治疗的使用率仍然较低（约10%），占所有AIS的90% 仅接受姑息治疗的受害者。因此，迫切需要提高药物的有效性和安全性。 溶栓和扩大溶栓到更多的AIS受害者。 UNandUP发明了一种新型的基于纳米颗粒的溶栓平台，可以安全地加速阿替普酶， AIS相关血凝块，从而克服已知可阻止阿替普酶 到达闭塞处。该平台通过以下方式克服了这一障碍：1）将阿替普酶缀合的磁性 纳米颗粒到达凝块表面的速度比正常的生物扩散快350倍以上（因此溶解开始 在数分钟内与数小时内），和2）在凝块表面机械混合阿替普酶， 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的升高）， 出血风险）。C3 i参与和FDA/监管会议确认了可能的CDER途径， 尽管比CDRH途径更快速和更昂贵，但产生了商业上有吸引力的药物组合物， 产品该平台对医院来说是负担得起的，不需要精确了解凝块的位置， 旨在支持轮辐和轮毂冲程中心之间的EMT转移，从而确保血栓切除术 没有延迟。一旦被证明安全有效，UNandUP的目标是将溶栓的益处扩展到 几乎所有的70万AIS受害者，这是目前治疗的10倍多。通过利用UNANDUP之前的 成功开发磁性纳米颗粒和便携式磁体系统，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。

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.