A reversible aptamer based therapeutic to treat stroke

基于可逆适体的中风疗法

• 批准号: 10176561
• 负责人: Shahid Nimjee
• 金额: $ 165.62万
• 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 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10176561
• 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; 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; detection method; 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.

项目总结/摘要 导致中风和心肌梗死的闭塞性动脉血栓形成导致约1300万人死亡 在世界各地。在过去的二十年里，重组组织型纤溶酶原激活剂（rTPA） 仍然是唯一被批准用于治疗急性缺血性中风的药物。不幸的是，接受rTPA的患者 有症状的出血显著增加，转换率为6.4%。此外，rTPA仅 在动脉血栓中实现平均~30%的再通，动脉血栓通常富含血小板， 众所周知对rTPA有抵抗力这方面的证据见于最近的一项研究， 大血管闭塞（LVO）卒中并接受rTPA治疗，仅10%的患者显示血管再通。 时间rTPA治疗的局限性导致只有约5%的患者实际接受药物治疗。因此 迫切需要开发抗血栓形成剂，其：1）防止闭塞性血栓形成，2） 再通急性动脉闭塞和3）预防再狭窄，所有这些都具有上级 rTPA。 血管性血友病因子（VWF）是抗血栓治疗的最佳靶点。在高剪切下， 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， 以及GPIIb-IIIa，导致血小板活化和聚集。VWF也自我关联，延伸到 在血管腔中，它不仅作为血小板的支架，而且还作为红细胞的支架。这些中央 这些过程最终导致动脉血栓形成，如在缺血性中风中所见。 适体是一类创新的药物分子，由寡核苷酸组成， 有效结合并抑制靶蛋白。Basking Biosciences Inc开发了一种RNA适体， 抑制VWF，命名为DTRI-031。它还设计了一种名为DTRI-025的逆转寡核苷酸， 在几分钟内迅速中和DTRI-031。DTRI-031可防止血栓形成，完全溶解血栓形成 在小型和大型动物中，与rTPA相比， 动脉血栓形成和中风的模型。目前，它已进入IND赋能研究的最后一个系列。DTRI-025 在小动物模型中在体外和体内快速逆转DTRI-031活性。本提案的总体目标是 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生产的DTRI-025进行GLP安全药理学和毒性研究的生物测定。的 该提案的目的是允许Basking Biosciences向FDA提交Pre-IND申请，并最终导致 与DTRI-031联合进行的首次人体试验。