Next Generation Therapeutics for Hemoglobinopathies

描述（由申请人提供）：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，构成了主要的全球健康负担，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，但通常在婴儿期被抑制到低水平。数十年的研究表明，胎儿血红蛋白的药物增强是一种有效的治疗策略，任何HbF和f细胞的增量增加都可以降低镰状细胞病或b-地中海贫血的严重贫血的严重程度。羟基脲（HU）是fda批准的治疗镰状细胞病的唯一药物，其有益效果主要是由于其增加HbF的能力，并不是所有患者都对其反应良好。可单独使用或与胡芦巴素联合使用的其他治疗方法将有利于严重未得到满足的医疗需求。在评估球蛋白疾病的新疗法时，一个令人困惑的问题是患者基础HbF水平的广泛变异性，这与不同的基因修饰谱有关，这些基因修饰谱会改变基线HbF水平并影响治疗反应。从分子模型研究和fda批准用于其他医疗条件的药物库的高通量筛选程序中，我们在报告基因检测中发现了以前未被识别的、高效的、诱导hbf的药物，并证实了它们在正常受试者培养的红细胞中的活性。本研究旨在确定三种候选药物中哪一种对不同基因修饰谱和基线HbF水平的基因型镰状细胞患者培养的红细胞最有效，以便选择最佳药物进行临床试验评估。我们的目的包括：目的一：确定3种候选疗法在不同基因修饰谱和HbF水平的基因型镰状细胞患者红系祖细胞的体外比较活性，并选择最佳药物用于临床

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.