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

基本信息

批准号：
10646311
负责人：
Shahid Nimjee
金额：
$ 48.21万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
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/10646311
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 Complex Cytolysis Data Encapsulated Endothelium Erythrocytes Event Factor VIII Fibrin Fibrinolytic Agents Genetic Glycoproteins Goals Hemorrhage Hour Hypertension In Vitro Infarction Institution Intracranial Hemorrhages Ischemic Stroke Laser Speckle Imaging Ligands Magnetic Resonance Imaging Measures Mechanics Mediating Mediator Morbidity - disease rate Mus Oligonucleotides Outcome Patients Pharmaceutical Preparations Plasma Platelet Activation 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 Vascularization Work aged aptamer artery occlusion behavior test clinical database comparison control design disability effective therapy endovascular thrombectomy functional improvement functional outcomes hypertensive improved improved outcome in vivo injured innovation mortality mouse model novel 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

项目摘要

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.

项目概要动脉血栓形成导致急性缺血性中风（AIS）是发病率和死亡率的主要原因重组组织纤溶酶原激活剂 (rtPA) 是唯一被批准用于治疗 AIS 的药物。不幸的是，只有约 5-10% 的 AIS 患者实际上接受了 rtPA 治疗。包括症状性颅内出血 (ICH) 的显着增加，这种情况的发生率高达 6.4% 此外，接受该药物治疗的患者中，rtPA 只能实现 10% 的血管再通。这些血栓通常富含血小板，对大血管闭塞（LVO）中风具有极强的抵抗力。 rtPA 迫切需要以下血栓形成剂： 1. 靶向参与血栓形成的关键蛋白。中风血栓结构，2. 使动脉闭塞再通，3. 安全性优于 rtPA。血管性血友病因子 (VWF) 是 AIS 治疗的最佳靶点，VWF 与糖蛋白 Ib (GPIb) 结合。血小板受体复合物 GPIb-IX-V 以及 GPIIb-IIIa，导致血小板活化和聚集。 VWF 还可以自我结合，延伸到血管腔中作为血小板和红细胞粘附的支架。这些过程导致动脉血栓形成，如我们的脑血栓初步数据所示。来自中风患者的研究表明，大多数凝块具有富含 VWF 的血小板壳，包裹着血栓核心，为与 rtPA 相关的动脉再通率低下提供了解释。适体是基于寡核苷酸的药物，能够以高亲和力和特异性抑制其靶蛋白。我们还分离并优化了一种可结合并抑制 VWF 的 RNA 适体 (DTRI-031)。我们设计了第二种寡核苷酸 (DTRI-025)，可在几分钟内完全逆转 DTRI-031 活性。小型和大型动物血栓形成模型的数据表明，DTRI-031 可以预防血栓比 rtPA 更好地形成和裂解完全形成的动脉闭塞该提案的总体目标是 1) AIS 患者血浆 VWF 升高与凝血 VWF 相关，2) 证明 DTRI-031 抑制 VWF 可以转化为对 AIS 患者的有效治疗。我们将测试以下假设：1) VWF 是 AIS 治疗的最佳目标，我们的初步数据显示。 LVO AIS 患者的血浆 VWF 显着升高，我们的初步数据重复了这些结果。在小鼠中风模型中的发现 2) DTRI-031 可有效地在体外溶解 AIS 血液样本中的凝块。此外，DTRI-025 在 AIS 中快速逆转 DTRI-031 活性。 3) DTRI-031 治疗通过增加 AIS 小鼠模型的结果来改善结果。我们的初步数据表明，血管再通、减少梗塞体积和改善功能恢复。与对照组相比，DTRI-031 治疗的小鼠中风后梗塞体积减少。通过减少脑出血、脑水肿形成和血脑屏障破坏来提高安全性 AIS 与 rtPA 的比较。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A canine thromboembolic model of anterior circulation large vessel occlusion stroke.

犬前循环大血管闭塞性中风的血栓栓塞模型。

DOI：
发表时间：
2023-04
期刊：
影响因子：
4
作者：
Zakeri, Amanda S;Wheeler, Debra G;Huttinger, Allyson;Carfora, Arianna;Kini, Aarushi;Stork, Taggart;Yacoub, Simon;Anderson, Cole;Joseph, Matthew;Shujaat, Mohammed T;Nimjee, Shahid M
通讯作者：
Nimjee, Shahid M

Technical and clinical success after venous sinus stenting for treatment of idiopathic intracranial hypertension using a novel guide catheter for access: Case series and initial multi-center experience.

使用新型引导导管进行静脉窦支架置入术治疗特发性颅内高压后的技术和临床成功：病例系列和初步多中心经验。

DOI：
发表时间：
2022-11-17
期刊：
影响因子：
0
作者：
Zyck, Stephanie;Malik, Muhammad;Webb, Matthew;Mohammed, Marwa;Powers, Ciaran J;Birnbaum, Lee;Hawk, Harris;Brinjikji, Waleed;Nimjee, Shahid M
通讯作者：
Nimjee, Shahid M

Neoadjuvant Arterial Embolization of Spine Metastases Associated With Improved Local Control in Patients Receiving Surgical Decompression and Stereotactic Body Radiotherapy.

脊柱转移瘤的新辅助动脉栓塞与接受手术减压和立体定向放射治疗的患者局部控制的改善相关。

DOI：
发表时间：
2023-03-02
期刊：
影响因子：
4.8
作者：
Damante Jr, Mark A;Gibbs, David;Dibs, Khaled;Palmer, Joshua D;Raval, Raju;Scharschmidt, Thomas;Chakravarti, Arnab;Bourekas, Eric;Boulter, Daniel;Thomas, Evan;Grecula, John;Beyer, Sasha;Xu, David;Nimjee, Shahid;Youssef, Patrick;Lonser, Russe
通讯作者：
Lonser, Russe

Stroke and Neurogenesis: Bridging Clinical Observations to New Mechanistic Insights from Animal Models.

中风和神经发生：将临床观察与动物模型的新机制见解联系起来。

DOI：
发表时间：
2022-12-03
期刊：
影响因子：
6.9
作者：
Passarelli, Joshua P;Nimjee, Shahid M;Townsend, Kristy L
通讯作者：
Townsend, Kristy L

Correlation of von Willebrand factor and platelets with acute ischemic stroke etiology and revascularization outcome: an immunohistochemical study.

冯维勒布兰德因子和血小板与急性缺血性卒中病因和血运重建结果的相关性：一项免疫组织化学研究。

DOI：
发表时间：
2023-05
期刊：
影响因子：
0
作者：
Mereuta, Oana Madalina;Abbasi, Mehdi;Arturo Larco, Jorge L;Dai, Daying;Liu, Yang;Arul, Santhosh;Kadirvel, Ramanathan;Hanel, Ricardo A;Yoo, Albert J;Almekhlafi, Mohammed A;Layton, Kennith F;Delgado Almandoz, Josser E;Kvamme, Peter;Mendes Perei
通讯作者：
Mendes Perei