"REAL Answers" (Registry Expansion Analyses to Learn)

镰状细胞病(SCD)是一种遗传性的成人血红蛋白疾病，主要病症为 非洲裔美国人。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寿命缩短。SCD是一种孤儿疾病， 据估计，美国约有11万名患者遭受差异和歧视，健康状况改善 护理利用情况。直到最近，对这种疾病的管理在很大程度上局限于症状控制， 通过疼痛控制和输液。1998年，美国FDA批准羟基脲(HU)作为第一个 SCD的疾病调理疗法。随后对患有SCD的儿童和成人的研究证实， HU的有益作用，预防器官损害，降低死亡率。在过去五年中， 另外三种疾病修饰药物(L-谷氨酰胺、Voxelotor和Crizanlizumab)针对不同的 疾病病理生理学的机制已经得到FDA的批准，扩大了可用的 SCD的治疗性医疗设备。尽管这是一个值得欢迎的发展，但在 选择最有效的疾病修正疗法或组合，基于一系列亚 这种疾病的表型。从随机临床试验中获得的知识不太可能填补这一空白 涉及使用FDA批准的治疗方法。此应用程序寻求通过以下方式满足这一未满足的需求 NHLBI资助的基础设施(2400名SCD患者的预期登记)的优势 由遍布全美的八个中心组成的镰状细胞疾病实施联盟(2016-2022) 建议通过应用以下方法招募1200名患者(每个中心150名患者)来解决此问题 具体目标如下：1)比较新的疾病修饰疗法(L-谷氨酰胺，体素推进器， 和crizanlizumab)对SCD患者的临床结果的影响。我们将前瞻性地跟踪这些人 5年来，模拟关键的干预性III期SCD试验的数据收集方案和资格，以及 监测脏器损伤NT-proBNP心肺损害，尿白蛋白/肌酐肾功能， 血液溶血评分和症状负担(ASCQ-Me)2)确定遗传和基因组预测因素 通过a)整个外显子组测序和b)RNA序列(单核)对疾病修改疗法的反应 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.