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，由一个单一的氨基酸取代引起， 血红蛋白（Hb）影响大约10万美国人和全世界数百万人。血红蛋白结构异常 SCD导致红细胞（RBC）变得脆弱、僵硬和畸形（即，镰刀形）。慢性和过度 SCD中的RBC溶血和微血管闭塞导致多种不良病理效应， 包括活性氧的持续释放和过度的促炎反应， 天然NLRP 3炎性体途径的激活。对于那些患有SCD的人来说，这可能会成为一种恶性的 持续的促炎性状态促使进一步的微血管闭塞的周期，以及 从而导致长期炎症和进行性器官功能障碍。因此，SCD 患者的生活质量差，预期寿命缩短。疾病的复杂性 其临床表现需要能够靶向下游病理生理效应的治疗， 炎症起着关键作用。尽管不断出现的证据支持抗- 由于抗炎剂的存在，目前还没有专门批准用于治疗 SCD。NLRP 3炎性体是一种大的多聚体蛋白复合物，当被一组不同的 危险信号，通过激活半胱天冬酶-1启动深刻的先天性炎症反应， 促炎细胞因子IL-1β。很明显，炎性体途径的过度驱动在炎症反应中起关键作用。 SCD的发病机制。靶向NLRP 3炎性体抑制的有效和选择性药物将提供 最强大的炎症调节，使SCD患者受益，远高于使用 直接抑制胱天蛋白酶-1或IL-1β。这项提案的目标是开发我们的主要治疗候选人 YQ 128，一种高效口服炎性体抑制剂，可降低SCD的发病率并改善其预后 患者YQ 128是一种真正的先导候选药物，代表了多轮理性研究的高潮。 基于结构修饰以改善新化合物的效力、选择性和药物样理化性质 化学支架，其通过干扰炎性小体复合物与细胞之间的相互作用来阻断炎性小体复合物的形成， NLRP 3及其衔接蛋白ASC。基于一个重要的机构高度令人鼓舞的初步体外和 在体内数据，我们已经开发了一种研究策略，将证明这种新的概念验证功效 方法在转基因SCD小鼠的微血管闭塞模型。第一阶段研究将促进快速 过渡到确定性疗效试验和II期IND毒理学研究。