A novel thrombolytic targeting Von Willebrand Factor (VWF) to treat ischemic stroke

一种针对血管性血友病因子 (VWF) 治疗缺血性中风的新型溶栓药物

• 批准号: 10289825
• 负责人: Shahid Nimjee
• 金额: $ 56.4万
• 依托单位: OHIO STATE UNIVERSITY
• 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 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10289825
• 关键词: Acute; Adhesions; Affect; Affinity; Age; Age Factors; Alteplase; Animal Model; Architecture; Area; Autologous; Binding; Biological Specimen database; Blood; Blood - brain barrier anatomy; Blood Platelets; Blood coagulation; Blood specimen; Caring; Carotid Artery Thrombosis; Cell Adhesion; Cerebral Edema; Cerebral Thrombus; Cerebrum; Cessation of life; Clinical; Coagulation Process; Data; Encapsulated; Endothelium; Erythrocytes; Event; Factor VIII; Fibrin; Fibrinolytic Agents; Genetic; Glycoprotein Ib; Glycoproteins; Goals; Hemorrhage; Hour; Hypertension; In Vitro; Infarction; Institution; Intracranial Hemorrhages; Ischemic Stroke; Laser Speckle Imaging; Ligands; Magnetic Resonance Imaging; Measures; Mechanics; Mediating; Mediator of activation protein; Morbidity - disease rate; Mus; Oligonucleotides; Outcome; Patients; Pharmaceutical Preparations; Plasma; Platelet Activation; Platelet Glycoprotein GPIb-IX Complex; Platelet aggregation; Play; Pre-Clinical Model; Process; Production; Proteins; RNA; Recovery; Recovery of Function; Resistance; Risk; Role; Safety; Severities; Specificity; Stroke; Testing; Thrombectomy; Thrombin; Thromboembolism; Thrombosis; Thrombus; Time; Translating; Translational Research; Work; aged; aptamer; artery occlusion; base; behavior test; clinical database; design; disability; effective therapy; endovascular thrombectomy; functional outcomes; improved; improved outcome; in vivo; injured; innovation; mortality; mouse model; novel; oligomycin sensitivity-conferring protein; post stroke; prevent; programs; receptor; restenosis; scaffold; sex; stroke incidence; stroke intervention; stroke model; stroke patient; stroke symptom; stroke therapy; thromboembolic stroke; thrombolysis; von Willebrand Factor

PROJECT SUMMARY Arterial thrombosis resulting in acute ischemic stroke (AIS) is the leading cause of combined morbidity and mortality worldwide. Recombinant tissue plasminogen activator (rtPA) is the only drug approved to treat AIS. Unfortunately, only ~5-10% of patients who present with AIS actually receive rtPA. Risks of rtPA treatment include a significant increase in symptomatic intracranial hemorrhage (ICH), which occurs in up to 6.4% of patients who receive the drug. Moreover, rtPA only achieves 10% recanalization in patients who present with large vessel occlusion (LVO) stroke. These clots, which are commonly platelet-rich, are notoriously resistant to rtPA. A critical need exists to develop thrombolytic agents that: 1. target critical proteins involved in stroke clot architecture, 2. recanalize arterial occlusions, and 3. have a safety profile superior to rtPA. Von Willebrand Factor (VWF) is an optimal target for AIS treatment. VWF binds to glycoprotein Ib (GPIb) of the platelet receptor complex GPIb-IX-V as well as to GPIIb-IIIa, resulting in platelet activation and aggregation. VWF also self-associates, extending into the vessel lumen as a scaffold for platelet and red blood cell adhesion. These processes result in arterial thrombosis as seen in AIS patients. Our preliminary data of cerebral thrombi from stroke patients show that the majority of clots have a platelet shell rich with VWF encapsulating the thrombus core, providing an explanation for the poor arterial recanalization rate associated with rtPA. Aptamers are oligonucleotide-based drugs that inhibit their target proteins with high affinity and specificity. We have isolated and optimized an RNA aptamer that binds to and inhibits VWF (DTRI-031). We have also designed a second oligonucleotide (DTRI-025) that fully reverses DTRI-031 activity within minutes. Our data in small and large animal models of thrombosis demonstrates that DTRI-031 both prevents thrombus formation and lyses fully formed arterial occlusions better than rtPA. The overall goals of this proposal are to 1) correlate elevated plasma VWF to clot VWF in AIS patients and 2) demonstrate VWF inhibition by DTRI-031 can translate into an effective treatment for patients who present with AIS. We will test the hypotheses that 1) VWF is an optimal target for AIS treatment. Our preliminary data shows that LVO AIS patients have significantly elevated plasma VWF. Our preliminary data has replicated these findings in a murine model of stroke. 2) DTRI-031 effectively lyses clots in vitro in blood samples from AIS patients and in vivo in a murine model of stroke. Moreover, DTRI-025 rapidly reverses DTRI-031 activity in AIS in vitro and in vivo. 3) DTRI-031 treatment improves outcomes in a murine model of AIS by increasing recanalization, decreasing infarct volume, and improving functional recovery. Our preliminary data reveals that DTRI-031-treated mice have reduced post-stroke infarct volumes compared to control. Finally, DTRI-031 has an improved safety profile by decreasing ICH, cerebral edema formation and blood-brain-barrier breakdown after AIS compared to rtPA.

项目摘要 导致acchmicatimemtoke（AIS）的动脉血栓形成是病态结合的主要原因，并且 全球死亡率。 不幸的是，只有5-10％的AIS患者实际上接受了RTPA治疗的风险。 包括症状性颅内出血（ICH）的显着增加，最多发生在6.4％ 此外，RTPA的患者仅在与之相处的患者中获得了10％的重新疗法。 大容器闭塞（LVO）中风，通常是血小板富含的凝块 RTPA的存在至关重要的需要：1。靶向关键蛋白 卒中凝块结构，2。重新主导替代闭塞，3。具有比RTPA优于RTPA的安全性。 Von Willbrand因子（VWF）是AIS治疗的最佳靶标。 与GPIIB-IIIA有关的血小板受体复合物GPIB-IX-V，导致血小板激活和同意。 VWF也自缔合，延伸到血管腔中，作为血小板和红细胞粘附的支架。 如AIS患者所见，这些过程在动脉血栓形成中呈现。 中风患者表明，大多数凝块的血小板外壳壳富含与随身携带的伴随 血栓核心，为与RTPA相关的变化率差提供了解释。 适体是基于寡核苷酸的药物，它们具有高亲和力和特异性的靶蛋白 已经分离并优化了与VWF结合并抑制VWF的RNA适体（DTRI-031） 设计了第二个寡核苷酸（DTRI-025），可在我们的几分钟内完全逆转DTRI-031活动 大小动物模型的数据表明，DTRI-031都可以防止血栓 形成和裂解比RTPA更好地形成了替代的闭塞。 在AIS患者中相关的血浆VWF凝块VWF升高，2）证明DTRI-031抑制VWF可以 转化为患有AIS的患者的有效治疗方法。 我们将测试1）VWF是AIS治疗的最佳目标。 LVO AIS患者的血浆VWF显着升高。 中风模型中的发现。 此外，患者和体内的中风模型。 体内和体内3）DTRI-031治疗在AIS的鼠模型中改善 娱乐，减少梗塞量和提高功能恢复。 与对照相比，经DTRI-031处理的小鼠已经触及后梗塞的体积。 通过减少ICH，脑水肿的形成和击穿后的血液驾驶员细分，改善了安全性。 与RTPA相比，AIS。