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.

项目总结