A reversible aptamer based therapeutic to treat stroke

基于可逆适体的中风疗法

基本信息

批准号：
10011052
负责人：
Shahid Nimjee
金额：
$ 57.54万
依托单位：
BASKING BIOSCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-01 至 2022-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10011052
关键词：
Acute Adhesions Affect Alteplase Animal Experiments Animal Model Animals Base Ratios Binding Biological Assay Biological Sciences Bleeding time procedure Blood Platelets Blood coagulation Brain Injuries Canis familiaris Cerebral Thrombosis Cerebrum Cessation of life Clinical Clinical Data Clinical Trials Design Coagulation Process Contracts Detection Development Diagnostic radiologic examination Dose Drug Kinetics Elderly Epilepsy Erythrocytes Evaluation Fibrin Fibrinolytic Agents Formulation Generations Glycoprotein Ib Goals Hemorrhage Hemostatic function Inflammation Ischemia Ischemic Stroke Lead Ligands Measures Mechanics Methods Morbidity - disease rate Myocardial Infarction Names Oligonucleotides Operative Surgical Procedures Patient-Focused Outcomes Patients Pharmaceutical Preparations Pharmacology Phase Phase I Clinical Trials Physiological Platelet Activation Platelet Glycoprotein GPIb-IX Complex Platelet Glycoproteins Platelet aggregation Play Population Process Production Proteins RNA Regimen Resistance Risk Role Safety Series Stroke Therapeutic Thrombectomy Thrombelastography Thrombin Thrombosis Thrombus Time Toxic effect Toxicogenetics Toxicology Translating Validation acute stroke aptamer artery occlusion base commercialization design experience first-in-human functional outcomes improved improved outcome in vitro activity in vivo innovation mortality novel strategies oligomycin sensitivity-conferring protein platelet function pre-clinical preclinical development prevent receptor restenosis scaffold stroke model stroke patient stroke therapy von Willebrand Factor

项目摘要

PROJECT SUMMARY/ABSTRACT Occlusive arterial thrombosis leading to stroke and myocardial infarction contribute to ~13 million deaths around the world every year. Over the past two decades, recombinant tissue plasminogen activator (rTPA) has remained the only drug approved to treat acute ischemic stroke. Unfortunately, patients who receive rTPA have a significant increase in symptomatic hemorrhage with a conversion rate of 6.4%. Moreover, rTPA only achieves an average of ~30% recanalization in arterial thrombi, which are commonly platelet rich and are notoriously resistant to rTPA. Evidence for this was seen in a recent study in patients who presented with large vessel occlusion (LVO) stroke and received rTPA, demonstrated vessel recanalization only 10% of the time. The limitations of rTPA therapy result in only ~5% of patients actually receive the drug. Therefore, a critical need exists to develop anti-thrombotic agents that: 1) prevent occlusive thrombus formation, 2) recanalize acute arterial occlusions and 3) prevent restenosis, all with a superior safety profile than that of rTPA. Von Willebrand Factor (VWF) is an optimal target for anti-thrombotic therapy. Under high shear seen in thrombosis, VWF binds to glycoprotein Ib (GPIb) of the platelet receptor complex GPIb-IX-V (GPIb-IX-V) as well as to GPIIb-IIIa, resulting in platelet activation and aggregation. VWF also self-associates, extending into the vessel lumen where it serves not only as a scaffold for platelets but also red blood cells. These central processes ultimately result in arterial thrombosis as seen in ischemic stroke. Aptamers are an innovative class of drug molecules that consist of oligonucleotides that specifically and efficiently bind to and inhibit target proteins. Basking Biosciences Inc has developed an RNA aptamer that inhibits VWF, named DTRI-031. It has also designed a reversal oligonucleotide, named DTRI-025 that rapidly neutralizes DTRI-031 within minutes. DTRI-031 prevents thrombus formation, lyses fully formed arterial occlusions and reduces the radiographic burden of ischemia better than rTPA in small and large animal models of arterial thrombosis and stroke. It is currently in the final series of IND enabling studies. DTRI-025 rapidly reverses DTRI-031 activity in vitro and in vivo in small animal models. The overall goal of this proposal is to define the optimum dose of DTRI-025 to neutralize DTRI-031 in a large animal model and to develop a bioassay to perform GLP safety pharmacology and toxicity studies with GMP manufactured DTRI-025. The Aims of this proposal will allow Basking Biosciences to submit a Pre-IND application to FDA and ultimately lead to First In Human (FIH) trials in conjunction with DTRI-031.

项目概要/摘要导致中风和心肌梗塞的闭塞性动脉血栓导致约 1300 万人死亡在过去的二十年里，重组组织纤溶酶原激活剂（rTPA）每年都在世界各地出现。不幸的是，rTPA 仍然是唯一被批准用于治疗急性缺血性中风的药物。症状性出血显着增加，转化率为 6.4%。平均约 30% 的动脉血栓再通，这些血栓通常富含血小板，并且最近一项针对患有 rTPA 的患者的研究证明了这一点。大血管闭塞 (LVO) 中风并接受 rTPA，证明血管再通率仅为 10% rTPA 治疗的局限性导致只有约 5% 的患者实际接受了该药物治疗。迫切需要开发抗血栓药物：1) 预防闭塞性血栓形成，2) 重新疏通急性动脉闭塞并 3) 预防再狭窄，所有这些都比其他药物具有更高的安全性重组TPA。血管性血友病因子 (VWF) 是高剪切力下抗血栓治疗的最佳靶标。血栓形成时，VWF 与血小板受体复合物 GPIb-IX-V (GPIb-IX-V) 的糖蛋白 Ib (GPIb) 结合，如下所示以及 GPIIb-IIIa，导致血小板活化和聚集。血管腔不仅充当血小板的支架，而且还充当红细胞的支架。这些过程最终导致动脉血栓形成，如缺血性中风。适体是一类创新的药物分子，由寡核苷酸组成，具有特异性和 Basking Biosciences Inc 开发了一种 RNA 适体，可有效结合并抑制靶蛋白。抑制VWF，命名为DTRI-031，还设计了一种逆转寡核苷酸，命名为DTRI-025。在几分钟内迅速中和 DTRI-031 DTRI-031 防止血栓形成，溶解完全形成的血栓。在小型和大型动物中，动脉闭塞和减少缺血的放射学负担比 rTPA 更好动脉血栓形成和中风模型目前处于 DTRI-025 的最终系列研究中。在小动物模型中快速逆转 DTRI-031 的体外和体内活性该提案的总体目标。的目的是确定 DTRI-025 在大型动物模型中中和 DTRI-031 的最佳剂量，并开发一种使用 GMP 制造的 DTRI-025 进行生物测定，进行 GLP 安全药理学和毒性研究。该提案的目的是让 Basking Biosciences 向 FDA 提交 Pre-IND 申请，并最终领导与 DTRI-031 联合进行首次人体 (FIH) 试验。