A reversible aptamer based therapeutic to treat stroke

基于可逆适体的中风疗法

• 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
• 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

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.

项目摘要/摘要 闭塞动脉血栓形成导致中风和心肌梗塞约1300万人死亡 每年在世界各地。在过去的二十年中，重组组织纤溶酶原激活剂（RTPA）具有 仍然是唯一被批准治疗急性缺血性中风的药物。不幸的是，接受RTPA的患者 症状出血显着增加，转化率为6.4％。而且，仅RTPA 在动脉血栓中平均获得约30％的重新固定，通常是血小板富含的，并且是 众所周知，对RTPA有抵抗力。在最近的一项研究中看到了这一点的证据 大容器阻塞（LVO）中风并接受了RTPA，仅证明了船只的重新加续化10％ 时间。 RTPA疗法的局限性导致约5％的患者实际接受了该药物。因此， 存在批判性需求，以开发抗栓性剂：1）防止闭塞性血栓形成，2） 重新启动急性动脉闭塞和3）预防再狭窄，所有这些都具有优越的安全性。 RTPA。 冯·威尔布兰德因子（VWF）是抗栓性疗法的最佳靶标。在高剪的下 血栓形成，VWF与血小板受体复合物GPIB-IX-V（GPIB-IX-V）的糖蛋白IB（GPIB）结合为 以及GPIIB-IIIA，导致血小板激活和聚集。 vwf也是自求的，延伸到 它的容器管腔不仅可以用作血小板的支架，还可以用作红细胞。这些中心 过程最终导致动脉血栓形成，如缺血性中风所见。 APATMER是一种创新类的药物分子，由寡核苷酸组成，专门和 有效结合并抑制靶蛋白。 Basking Biosciences Inc开发了一种RNA apatamer 抑制VWF，名为DTRI-031。它还设计了一种反向寡核苷酸，名为DTRI-025 在几分钟内快速中和DTRI-031。 DTRI-031阻止了血栓形成，乳糖完全形成 小动物和大动物中的动脉闭塞和减少缺血的放射线燃烧更好 动脉血栓形成和中风的模型。目前，它是一系列IND促进研究。 DTRI-025 在小动物模型中，在体外和体内迅速逆转DTRI-031活性。该提议的总体目标 是定义DTRI-025的最佳剂量以中和大型动物模型中的DTRI-031并发展 使用GMP制造的DTRI-025进行GLP安全药理学和毒性研究的生物测定。这 该提案的目的将允许Basking Biosciences向FDA提交预定申请，并最终领导 首先在人类（FIH）试验中与DTRI-031一起进行。