Next Generation Therapeutics for Hemoglobinopathies

描述(申请人提供)：镰状细胞病和2-地中海贫血是人类最常见的遗传性单基因疾病，构成了全球主要的健康负担，每年花费美国医疗保健系统10亿美元。患者有慢性致残性发病率和早期死亡率。胎儿血红蛋白(HBF：A2，G2)是另一种内源性血红蛋白，通常存在于所有人类中，但在婴儿时期通常被抑制到低水平。数十年的研究表明，增加胎儿血红蛋白的药理作用是一种有效的治疗策略，因为HBF和F细胞的任何增加都可以降低镰状细胞疾病的严重程度或b地中海贫血的严重贫血。羟基脲(HU)是FDA批准的唯一治疗镰状细胞病的药物，其有益作用主要是由于其能够增加HBF，并不是所有患者都有良好的反应。额外的疗法，可以单独使用，也可以与HU联合使用，将使严重未得到满足的医疗需求受益。在评估珠蛋白紊乱的新疗法时，一个令人困惑的问题是患者基础HbF水平的广泛差异，这与不同的Geneti修饰剂谱有关，这些变化改变了基线HbF水平并影响治疗反应。从分子建模研究和FDA批准用于其他医疗条件的药物库的高通量筛选程序中，我们在报告基因分析中发现了以前未识别的、高效的HBF诱导药物，并证实了它们在正常受试者培养的红系细胞中的活性。本研究旨在确定三种候选治疗药物中哪一种对具有不同遗传修饰谱和基线HbF水平的基因分型镰状细胞患者培养的红系细胞最有效，以便选择最佳的药物(S)用于临床试验的评估。我们的目标包括：目的一：比较3种候选药物对不同遗传修饰谱和HBF水平的不同基因分型镰状细胞患者红系祖细胞的体外活性，并选择最适合临床的药物 测试目标二：开发一种最有效的治疗药物配方，用于在患者群体的临床试验中进行快速评估 与公共健康相关：这项提案将评估3种安全的口腔疗法，用于新的医疗用途：血红蛋白疾病、导致终生发病率和早期死亡的严重血液疾病、美国每年10亿美元的医疗负担以及全球高儿童死亡率。候选疗法已经被批准用于其他医疗条件，或处于后期测试阶段。在完成对患者细胞培养的拟议研究后，可以在患者群体中测试最有效的药物，并可以方便地将新的治疗方法应用于他们的医疗保健。

DESCRIPTION (provided by applicant): Sickle cell disease and 2-thalassemias are mankind's most common hereditary monogenic diseases, comprise a major global health burden, and cost the US healthcare system >$1 billion annually. Patients have chronic disabling morbidity and early mortality. Fetal hemoglobin (HbF: a2,g2) is another endogenous type of hemoglobin normally present in all humans, but is normally suppressed in infancy to low levels. Pharmacologic augmentation of fetal hemoglobin is established as an effective therapeutic strategy, as decades of research have shown that any incremental increase in HbF and F-cells reduce the severity of sickle cell disease or the severe anemia of the b-thalassemias. Hydroxyurea (HU) is the sole FDA-approved drug for treatment of sickle cell disease, its beneficial effects are due primarily to its ability to increase HbF, and not all patients respond favorably. Additional therapeutics, which can be used alone or in combination with HU, would benefit a serious unmet medical need. A confounding issue in evaluating new therapies in the globin disorders is the wide variability in patients' basal HbF levels, related to different geneti modifier profiles which alter baseline HbF levels and affect therapeutic responses. From molecular modeling studies and a high-throughput screening program of a library of drugs which are FDA-approved for other medical conditions, we discovered previously unrecognized, highly potent, HbF-inducing drugs in reporter gene assays and confirmed their activity in erythroid cells cultured from normal subjects. This proposal is to determine which of three therapeutic candidates is most potent in erythroid cells cultured from genotyped sickle cell patients with different genetic modifier profiles and baseline HbF levels, in order to select optimal agent(s) fo evaluation in clinical trials. Our aims include: Aim I: To determine the comparative in vitro activity of 3 candidate therapeutics in erythroid progenitors from genotyped sickle cell patients with different genetic modifier profiles and HbF levels and to select the optimal drug for clinical testing Aim II: To develop a medicinal formulation of the most active therapeutic for rapid evaluation in clinical trials in the patient population PUBLIC HEALTH RELEVANCE: This proposal will evaluate 3 safe oral therapeutics for a new medical use in hemoglobin diseases, serious blood diseases which confer life-long morbidity and early mortality, an annual US healthcare burden of >$1 Billion, and high childhood mortality internationally. The candidate therapeutics are already approved for other medical conditions, or in late-stage testing. Upon completion of the proposed studies on patients' cells in culture, the most potent agent can be tested in the patient populations, and a new therapy can be expediently applied to their medical care.