Pharmacologic Inhibition of NLRP3 Inflammasome-Dependent Injury following Vaso-occlusion in Sickle Cell Disease

镰状细胞病血管闭塞后 NLRP3 炎症小体依赖性损伤的药理学抑制

• 批准号: 10258844
• 负责人: David Richard Light
• 金额: $ 29.52万
• 依托单位: MIND BIOSCIENCES LLC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10258844
• 关键词: Abnormal Hemoglobins; Acclimatization; Acute; Acute-Phase Proteins; Adaptor Signaling Protein; Adverse effects; Affect; Air; American; Amino Acid Substitution; Anti-Inflammatory Agents; Antisickling Agents; Autopsy; Biological; Biological Markers; Blood; Blood specimen; CASP1 gene; Cardiac; Cell Adhesion Molecules; Cessation of life; Chemicals; Chronic; Clinical; Complex; Control Groups; Data; Development; Disease; Dose; Drug Targeting; Erythrocytes; Exposure to; Functional disorder; Generations; Glomerular Filtration Rate; Goals; Hematology; Hemoglobin; Hemolysis; Hereditary Disease; Histopathology; Hour; Hypoxia; Immunohistochemistry; In Vitro; Individual; Inflammasome; Inflammation; Inflammatory; Inflammatory Response; Injury; Interleukin-1 beta; Investigational Drugs; Investigational New Drug Application; Knock-out; Lead; Life; Life Expectancy; Mammals; Modeling; Modification; Monitor; Morbidity - disease rate; Mus; Nature; Oral; Organ; Organ failure; Pain; Pathogenesis; Pathologic; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Phase; Plasma; Play; Polymers; Positioning Attribute; Prognosis; Property; Puncture procedure; Quality of life; Randomized; Reactive Oxygen Species; Research; Sickle Cell Anemia; Signal Transduction; Specimen; Stress; Stress Tests; Structural defect; Structure; Tablets; Temperature; Tissue Sample; Tissues; Toxicology; Transgenic Organisms; Treatment Cost; Up-Regulation; Veins; Weight; base; cytokine; drug candidate; drug discovery; efficacy study; efficacy testing; hemodynamics; human disease; improved; in vivo; inflammatory modulation; inhibitor/antagonist; innovation; intravital microscopy; member; normoxia; novel; novel strategies; novel therapeutic intervention; phase 1 study; premature; protein complex; response; sample collection; scaffold; sickling; small molecule; therapeutic candidate

Sickle cell disease (SCD), a devastating chronic inherited disorder caused by a single amino acid substitution in hemoglobin (Hb), affects approximately 100,000 Americans and millions worldwide. Structurally abnormal Hb in SCD causes red blood cells (RBCs) to become fragile, rigid, and malformed (i.e., sickled). Chronic and excessive RBC hemolysis and microvascular occlusion in SCD results in a diverse set of adverse pathologic effects, including persistent release of reactive oxygen species and an exaggerated pro-inflammatory response from activation of the innate NLRP3 inflammasome pathway. For those suffering from SCD, this can become a vicious cycle in which a persistent pro-inflammatory state precipitates further microvascular occlusion, and consequently, contributes to long-standing inflammation and progressive organ dysfunction. Consequently, SCD patients suffer from a poor quality of life and have a reduced life expectancy. The complex nature of the disease and its clinical manifestations require therapies that can target downstream pathophysiologic effects, of which inflammation plays a key role. Although evidence continues to emerge supporting the potential benefit of anti- inflammatory agents, there are currently no anti-inflammatory drugs approved specifically for the treatment of SCD. The NLRP3 inflammasome is a large multimeric protein complex that, when triggered by a diverse set of danger signals, initiates a profound innate inflammatory response by activating caspase-1 and the proinflammatory cytokine IL-1β. It is clear that excessive drive of the inflammasome pathway plays a key role in the pathogenesis of SCD. A potent and selective drug targeting NLRP3 inflammasome inhibition would provide the most robust inflammatory modulation to benefit SCD patients, far above that which can be achieved with direct inhibition of caspase-1 or IL-1β. The goal of this proposal is to develop our lead therapeutic candidate YQ128, a highly potent oral inflammasome inhibitor to reduce morbidity and improve the prognosis for SCD patients. YQ128 is a bona fide lead drug candidate that represents the culmination of multiple rounds of rational structure-based modification to improve potency, selectivity, and drug-like physiochemical properties of a novel chemical scaffold that blocks formation of the inflammasome complex by interfering with the interaction between NLRP3 and its adaptor protein ASC. Based on a significant body of highly encouraging preliminary in vitro and in vivo data, we have developed a research strategy that will demonstrate proof-of-concept efficacy for this novel approach in a model of microvascular occlusion in transgenic SCD mice. This Phase I study will facilitate a rapid transition to definitive efficacy testing and IND-enabling toxicology studies in Phase II.

镰状细胞病 (SCD) 是一种毁灭性的慢性遗传性疾病，由单个氨基酸取代引起 血红蛋白 (Hb) 影响着大约 100,000 名美国人以及全世界数百万人的 Hb 结构异常。 SCD 导致红细胞 (RBC) 变得脆弱、僵化和畸形（即慢性和过度镰状）。 SCD 中的红细胞溶血和微血管闭塞会导致多种不良病理反应， 包括活性氧的持续释放和过度的促炎反应 对于患有 SCD 的人来说，先天性 NLRP3 炎性体途径的激活可能会成为一种恶性疾病。 持续的促炎状态导致进一步的微血管闭塞的循环，以及 因此，会导致长期炎症和进行性器官功能障碍（SCD）。 患者的生活质量较差，预期寿命缩短。该疾病的性质很复杂。 及其临床表现需要针对下游病理生理效应的治疗，其中 尽管不断出现的证据支持抗-炎症的潜在益处。 炎症药物，目前还没有批准专门用于治疗的抗炎药物 SCD 是一种大型多聚蛋白复合物，当被多种不同的物质触发时，该复合物会被激活。 危险信号，通过激活 caspase-1 和 促炎细胞因子 IL-1β 很明显，炎症小体途径的过度驱动在其中起着关键作用。 一种有效的、选择性的靶向 NLRP3 炎性体抑制的药物将提供 SCD 的发病机制。 使 SCD 患者受益的最强大的炎症调节，远远高于通过 直接抑制 caspase-1 或 IL-1β 该提案的目标是开发我们的主要治疗候选药物。 YQ128，一种高效口服炎性体抑制剂，可降低 SCD 的发病率并改善预后 YQ128是真正的先导候选药物，代表了多轮理性研究的顶峰。 基于结构的修饰，以提高新型药物的效力、选择性和类药物理化性质 通过干扰之间的相互作用来阻止炎性体复合物形成的化学支架 NLRP3 及其接头蛋白 ASC 基于非常令人鼓舞的体外和体外实验。 根据体内数据，我们制定了一项研究策略，将证明这款小说的概念验证功效 转基因 SCD 小鼠微血管闭塞模型中的方法这一第一阶段研究将促进快速进展。 在第二阶段过渡到明确的功效测试和支持 IND 的毒理学研究。