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; 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），这是一种由单个氨基酸取代引起的毁灭性慢性遗传疾病 血红蛋白（HB）影响了全球约100,000名美国人和数百万的美国人。结构异常HB SCD会导致红细胞（RBC）变得脆弱，僵硬和畸形（即镰状）。慢性和过度 SCD中的RBC溶血和微血管闭塞会导致多种不良病理性效应， 包括持续释放活性氧和来自 先天性NLRP3炎性途径的激活。对于那些患有SCD的人，这可能会变成恶性 持续性的促炎状态珍贵的循环呈现进一步的微血管阻塞，并且 因此，有助于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，预期寿命降低。疾病的复杂性质 它的临床表现需要靶向下游病理生理作用的疗法，其中 炎症起着关键作用。尽管证据继续出现，以支持反抗的潜在利益 炎症剂，目前尚无专门用于治疗的抗炎药 scd。 NLRP3炎症体是一种大型的多蛋白质复合物，当由一组多样的触发时 危险信号，通过激活caspase-1和 促炎性细胞因子IL-1β。显然，炎性途径的多余驱动在 SCD的发病机理。潜在的选择性药物靶向NLRP3炎症体抑制作用将提供 最强大的炎症调节使SCD患者受益，远高于可以实现的炎症患者 直接抑制caspase-1或IL-1β。该提议的目的是培养我们的主要治疗候选人 YQ128，一种高潜在的口腔炎性抑制剂，可降低发病率并改善SCD的预后 患者。 YQ128是一个真正的铅药物候选药物，代表了多轮合理的高潮 基于结构的修饰，以提高新颖的效力，选择性和药物样理化学特性 化学脚手架通过与 NLRP3及其衔接蛋白ASC。基于大量令人鼓舞的体外初步和 在体内数据中，我们制定了一种研究策略，该策略将证明这本小说的概念验证效率 在转基因SCD小鼠中微血管闭塞模型中的方法。这一阶段I研究将有助于快速 在第二阶段的确定性有效性测试和毒理学研究过渡。