"REAL Answers" (Registry Expansion Analyses to Learn)

镰状细胞病（SCD）是一种遗传性成人血红蛋白疾病，主要累及 非裔美国人突变的血红蛋白，Hb S，在脱氧时聚合，导致 红细胞流变学受损、微血管闭塞、慢性炎症状态和慢性溶血 贫血，最终导致慢性器官损伤和预期寿命缩短。SCD是一种孤儿病， 据估计，美国约有110，000名患者遭受不平等和歧视， 护理利用率直到最近，这种疾病的管理主要限于症状控制， 疼痛控制和输血1998年，美国FDA批准羟基脲（HU）作为第一个 SCD的疾病修饰疗法。随后对SCD儿童和成人的研究证实， HU的有益效果，预防器官损伤和降低死亡率。在过去的五年里， 三种额外的疾病修饰药物（L-谷氨酰胺，voxelotor和crizanlizumab）靶向不同的 疾病病理生理学中的机制已经被FDA批准， SCD的治疗设备虽然这是一个值得欢迎的发展，但在知识方面存在差距。 选择最有效的疾病修饰疗法或组合，基于亚 疾病的表型。这一空白不太可能通过随机临床试验获得的知识来填补 涉及使用FDA批准的疗法。本申请旨在满足这一未满足的需求， 由NHLBI资助的基础设施（2400名SCD患者的前瞻性登记研究）的优势 镰状细胞病实施联盟（2016-2022）由美国各地的八个中心组成。 建议通过应用以下方法入组1200例患者（每个中心150例患者）来解决该问题： 以下具体目的：1）比较新的疾病改善疗法（L-谷氨酰胺，voxelotor， 和crizanlizumab）对SCD患者临床结果的影响。我们将前瞻性地跟踪这些人 5年，模拟关键的干预性III期SCD试验的数据收集方案和合格性，以及 监测器官损伤NT-proBNP的心脏和肺损伤，监测尿白蛋白/肌酐比值的肾功能， 血液溶血评分以及症状负荷（ASCQ-Me）2）鉴定遗传和基因组预测因子 通过a）全外显子组测序和B）RNA seq（单核细胞 细胞、网状细胞、血小板）;以及3）将研究数据整合到CureSCi元数据目录中，以增强未来的交叉 研究分析。

Sickle cell disease (SCD) is an inherited disorder of human adult hemoglobin, which primarily afflicts Americans of African descent. The mutant hemoglobin, Hb S, polymerizes upon deoxygenation, leading to impaired red blood cell rheology, microvascular occlusion, chronic inflammatory state, and chronic hemolytic anemia, culminating in chronic organ damage and a shortened life expectancy. SCD is an orphan disease, with an estimated ~110,000 patients in the U.S. who suffer from disparities and discrimination and increased health care utilization. Until recently, the management of the disease has been largely confined to symptom control, with pain management and transfusions. In 1998, the U.S. FDA approved hydroxyurea (HU) as the first disease modifying therapy for SCD. Subsequent studies in children and adults with SCD has confirmed the beneficial effects of HU, with prevention of organ damage and decrease in mortality. In the past five years, three additional disease modifying drugs (L-glutamine, voxelotor, and crizanlizumab) targeting different mechanisms in disease pathophysiology have been approved by the FDA, broadening the available therapeutic armamentarium for SCD. Although this is a welcomed development, knowledge gaps exist on the choice of the most effective disease modifying therapy or combinations, based on a spectrum of sub- phenotypes of the disease. This gap is unlikely to be filled by knowledge gained from randomized clinical trials involving the use of FDA approved therapies. This application seeks to meet this unmet need by taking advantage of the infrastructure (prospective Registry of 2400 SCD patients) provided by the NHLBI funded Sickle Cell Disease Implementation Consortium (2016-2022) consisting of eight Centers throughout U.S. We propose to approach this problem by enrolling 1200 patients (150 patients from each Center) by applying the following specific aims: 1) Compare the effect of novel disease modifying therapies (L-glutamine, voxelotor, and crizanlizumab) on clinical outcomes in individuals with SCD. We will follow these individuals prospectively for 5 years, emulating data collection protocols and eligibility from key, interventional phase III SCD trials, and monitor organ injury NT-proBNP for heart and lung injury, urine albumin/creatinine ratio for kidney function, hemolysis score for blood, as well as symptom burden (ASCQ-Me) 2) Identify genetic and genomic predictors of response to disease modifying therapies, by a) whole exome sequencing and b) RNA seq (mononuclear cells, retics, platelets); and 3) integrate study data into the CureSCi metadata catalog to enhance future cross study analyses.