Development of a non-Factor small molecule, oral, prophylactic and hemostasis balanced therapy for treatment of clotting disorders including hemophilia A/B

开发非因子小分子、口服、预防性和止血平衡疗法，用于治疗包括血友病 A/B 在内的凝血障碍

• 批准号: 10384995
• 负责人: Makarand Prabhakar Gore
• 金额: $ 30万
• 依托单位: YEWSAVIN, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10384995
• 关键词: Activated Partial Thromboplastin Time measurement; Address; Adverse event; Antibodies; Anticoagulants; Antithrombins; Apigenin; Artificial Intelligence; Biological Assay; Blood Coagulation Disorders; Blood Coagulation Factor; Blood coagulation; Chalcones; Chemicals; Coagulants; Coagulation Process; Complex; Complication; Crystallization; Cytolysis; Development; Dose; Equilibrium; F8 gene; Factor IX; Factor V; Factor VIII; Fee-for-Service Plans; Fibrinolytic Agents; Flavones; Flavonoids; Formulation; Fractionation; Generations; Goals; Hemophilia A; Hemorrhage; Hemostatic Agents; Hemostatic function; Heparin; Impairment; In Vitro; Inherited; Injectable; Injections; Intravenous; Investigational Therapies; Knockout Mice; Knowledge; Luteolin; Measures; Methods; Michigan; Oral; Pathway interactions; Patients; Pharmacologic Substance; Plant Extracts; Plants; Preparation; Prevention; Process; Prophylactic treatment; Protein C; Proteins; Prothrombin time assay; Rattus; Rotation; Solubility; Solvents; Structure; System; TFPI; Testing; Therapeutic Agents; Thrombin; Thromboplastin; Thrombosis; Time; Translating; United States National Institutes of Health; Universities; VWF gene; animal safety; base; combinatorial; efficacy study; healing; ineffective therapies; inhibitor; lead optimization; lead series; mouse model; novel; phase 2 study; prevent; professor; prophylactic; response; safety study; single molecule; small molecule; subcutaneous; treatment strategy; wound healing

ABSTRACT Hemophilia, A, B, C, and vwF are inherited bleeding disorders resulting from a partial or complete deficiency of Factor VIII (FVIII) or Factor IX (FIX), respectively. Factor-based therapies involve the administration of exogenous clotting factor concentrates with the aim of achieving the necessary levels of circulating protein. However, factor-based therapies present the complication of inhibitors (antibodies) inactivating the therapeutic agents, rendering treatments ineffective. Current investigational therapies seek to diminish the anti-clotting natural control factors Protein C, Anti-thrombin and Tissue Factor Protein Inhibitor (TFPI-inhibitor) in order to enhance clotting in patients with impaired clotting. This approach has significant challenges since the coagulation process must remain extremely well-balanced and is important to make sure that prevention of hemorrhage by enhancing clotting does not result in inadvertent thrombosis. Furthermore, most of these therapies are administered in bi-weekly injections, subcutaneous or intravenous, and adverse events relating to injectables remain a concern. Our overarching goal was to understand the remarkable effects of traditionally used plant extracts on wound healing and the balance between hemostasis and thrombosis, and their application in developing an oral treatment for hemophilia. YewSavin’s plant-derived pair of coagulant and anti-coagulant molecules result in the best balance of hemostasis and thrombosis. This small molecule oral, the first in such class, treatment strategy, two Complementary Components (CC_2), consisting of Chalcones (pro-coagulant) and Flavones (anti- coagulant), that could potentially revolutionize hemophilia and anti-thrombotic treatments for clotting and thrombotic disorders alike by promoting blood clotting processes without causing thrombosis. In preliminary studies, bio-assays of clotting and healing times guided our initial fractionation assays towards identifying single molecule entities that promoted clotting and healing. We triangulated molecules for hemophilia treatment and accelerated healing using our proprietary artificial intelligence (AI), structure match (SAR), and experimental verification by bioassay guided fractionation ability. Using a Factor VIII knockout (KO) mouse model, we demonstrated that our identified CC_2 molecules cause significant improvement in clotting time, in normal rats and in Factor VIII KO mice. These results demonstrate that CC_2 is not Factor VIII dependent and is also more efficient than the first line therapy currently used, injection of Factor VIII. Finally, there are currently no known anti-thrombin small molecule agents. According to our preliminary results, the mechanism of action seems to be the dose-dependent reversal of the Heparin-Antithrombin complex that blocks coagulation. This project proposed by YewSavin, Inc. will apply knowledge of clotting processes gained from plant molecules to address the challenges of hemostasis-thrombosis balanced therapy and to advance discovery of a class of small molecule, non-immunogenic, compounds for oral prophylactic treatment in hemophilia.

抽象的 血友病，A，B，C和VWF是由于部分或完全缺乏症而遗传的出血性疾病 因子VIII（FVIII）或因子IX（修复）。基于因素的疗法涉及管理 外源服装因子浓缩，目的是达到必要的循环蛋白水平。 但是，基于因子的疗法呈现抑制剂（抗体）灭活治疗的并发症 代理人，使治疗无效。当前的研究疗法旨在减少反闭合 自然控制因子蛋白C，抗凝血酶和组织因子蛋白抑制剂（TFPI抑制剂），以便 增强衣服受损患者的衣服。自凝结以来，这种方法面临着巨大的挑战 过程必须保持非常平衡，并且重要的是要确保预防出血 增强衣服不会导致无意的血栓形成。此外，这些疗法中的大多数是 每两周注射，皮下或静脉注射和与注射剂有关的不良事件 仍然是一个问题。 我们的总体目标是了解传统使用的植物提取物对伤口的显着影响 愈合和止血和血栓形成之间的平衡，以及它们在开发口腔中的应用 血友病的治疗。叶索文的植物衍生的一对凝结剂和抗凝血分子导致 止血和血栓形成的最佳平衡。这个小分子的口服，第一个是这样的治疗 策略，两个互补的成分（CC_2），由Chalcones（促凝剂）和黄酮（抗凝蛋白）组成 凝结剂），这可能会彻底改变血友病和抗栓性治疗，以闭合和 血栓性疾病通过促进血液服装过程而不会引起血栓形成。 在初步研究中，结束和康复时间的生物测定指导了我们的最初分馏评估 识别促进衣服和愈合的单分子实体。我们为血友病的分子进行了三角分子 使用我们的专有人工智能（AI），结构匹配（SAR）和 通过生物测定指导分馏能力进行实验验证。使用因子VIII敲除（KO）鼠标 模型，我们证明了我们所识别的CC_2分子在关闭时间中显着改善 正常大鼠和VIII KO小鼠。这些结果表明CC_2不是VIII因子依赖性因素，并且 也比当前使用的第一线治疗（注射VIII因子注射）更有效。最后，目前有 没有已知的抗凝血酶小分子剂。根据我们的初步结果，作用机理 似乎是阻断凝血的肝素 - 抗凝血酶复合物的剂量依赖性逆转。 Yewsavin，Inc。提出的这个项目将应用对工厂获得的关闭过程的知识 分子应对止血性息肉疗法的挑战，并提高发现 小分子类，非免疫原性，用于血友病中预防性治疗的化合物。