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.

摘要 血友病、A、B、C和VWF是遗传性出血性疾病，由部分或完全缺乏 因子VIII(FVIII)或因子IX(FIX)。基于因子的治疗包括给药 外源性凝血因子浓缩的目的是达到必要的循环蛋白水平。 然而，基于因子的治疗呈现抑制物(抗体)灭活治疗性的并发症。 代理商，使治疗无效。目前的研究疗法试图减少抗凝血 天然控制因子蛋白C、抗凝血酶和组织因子蛋白抑制物(TFPI-抑制物) 增强凝血功能受损患者的凝血功能。这种方法有很大的挑战，因为凝结 过程必须保持极好的平衡，并重要的是确保通过 增强凝血功能不会导致无意中的血栓形成。此外，这些疗法大多是 每两周一次皮下或静脉注射，以及与注射剂有关的不良事件 仍然是一个令人担忧的问题。 我们的首要目标是了解传统使用的植物提取物对伤口的显著影响。 愈合、止血与血栓形成的平衡及其在口腔修复中的应用 治疗血友病。YewSavin的植物衍生凝血剂和抗凝血剂分子对导致了 止血和血栓形成的最佳平衡。这种小分子口服，在这样的班级中是第一次治疗 策略，两个互补成分(CC_2)，由查尔酮(促凝剂)和黄酮类(抗凝血剂)组成 凝血剂)，这可能会给血友病和抗血栓治疗带来革命性的变化 血栓性疾病类似于促进血液凝结过程而不导致血栓形成。 在初步研究中，凝血和愈合时间的生物分析指导我们最初的分级分析 鉴定促进凝血和愈合的单分子实体。我们对血友病的分子进行了三角测量 使用我们专有的人工智能(AI)、结构匹配(SAR)和 通过生物测定指导分馏能力的实验验证。使用因子基因敲除(KO)小鼠 模型中，我们证明了我们识别的CC_2分子显著缩短了凝血时间，在 正常大鼠和凝血因子VIII KO小鼠。这些结果表明，CC_2不依赖于因子VIII，而且 也比目前使用的一线疗法，注射因子VIII更有效。最后，目前有 目前尚无已知的抗凝血酶小分子药物。根据我们的初步结果，作用机制 似乎是剂量依赖性地逆转了肝素-抗凝血酶复合体，从而阻止了凝血。 这个由YewSavin，Inc.提出的项目将应用从植物获得的凝血过程知识 分子，以应对止血-血栓平衡治疗的挑战，并推进一种 一类小分子、非免疫原性化合物，用于血友病口服预防治疗。