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

镰状细胞病(SCD)是一种破坏性的慢性遗传性疾病，由体内单一氨基酸替代引起 血红蛋白(Hb)，影响大约10万美国人和全球数百万人。结构异常的Hb SCD导致红细胞(RBC)变得脆弱、僵硬和畸形(即，镰状)。慢性和过度 SCD中的红细胞溶血和微血管闭塞导致一系列不利的病理效应， 包括持续释放活性氧物种和夸大的促炎反应 激活先天的NLRP3炎症体途径。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，会导致长期的炎症和进行性器官功能障碍。因此，SCD 患者的生活质量很差，预期寿命也会缩短。这种疾病的复杂性质 其临床表现需要针对下游病理生理效应的治疗，其中 炎症起着关键作用。尽管不断涌现的证据支持反兴奋剂的潜在好处 炎性药物，目前还没有批准的抗炎药物专门用于治疗 SCD。NLRP3炎症体是一个大型的多聚体蛋白质复合体，当被一系列不同的 危险信号，通过激活caspase-1和 促炎症细胞因子IL-1β。很明显，炎症体途径的过度驱动在 SCD的发病机制。一种针对NLRP3炎症体抑制的有效和选择性药物将提供 使SCD患者受益的最强大的炎症调节，远远超过 直接抑制caspase-1或IL-1β。这项提议的目标是开发我们的主要候选治疗药物 YQ128是一种高效的口服炎性小体抑制剂，可降低SCD的发病率并改善预后 病人。YQ128是一个真正的领先候选药物，代表着多轮理性 基于结构的修饰以提高一种新型药物的效力、选择性和类药物的物理化学性质 通过干扰炎症小体之间的相互作用来阻止炎症体复合体的形成的化学支架 NLRP3及其接头蛋白Asc。基于一组非常鼓舞人心的初步体外试验和 在活体数据中，我们已经开发了一种研究策略，将展示这部小说的概念验证有效性 转基因SCD小鼠微血管闭塞模型的建立。这项第一阶段研究将促进快速 在第二阶段过渡到最终疗效测试和启用IND的毒理学研究。

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.