Next Generation Therapeutics for Hemoglobinopathies

血红蛋白病的下一代治疗方法

• 批准号: 8250888
• 负责人: SUSAN Park PERRINE
• 金额: $ 49.13万
• 依托单位: PHOENICIA BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8250888
• 关键词: Adult; Affect; Anemia; Biochemical; Biological Assay; Caring; Cell Culture Techniques; Cells; Childhood; Chronic; Clinical; Clinical Trials; Development; Disease; Dose; Drug Formulations; Epidemiologic Studies; Erythroid; Erythroid Cells; Evaluation; FDA approved; Fetal Hemoglobin; Generations; Genes; Genetic; Genotype; Globin; Healthcare; Healthcare Systems; Hematological Disease; Hemoglobin; Hemoglobin A; Hemoglobinopathies; Hereditary Disease; Human; In Vitro; Inherited; Lead; Libraries; Life; Medical; Messenger RNA; Modeling; Molecular Models; Morbidity - disease rate; Mutation; Oral; Patients; Pharmaceutical Preparations; Population; Production; Reporter; Reporter Genes; Research; Selection Criteria; Severities; Sickle Cell; Sickle Cell Anemia; Staging; Structure; Syndrome; System; Testing; Thalassemia; Therapeutic; Therapeutic Agents; base; clinical efficacy; comparative; cost; fetal globin; global health; high throughput screening; hydroxyurea; in vitro activity; infancy; molecular modeling; mortality; nonhuman primate; novel therapeutics; patient population; progenitor; programs; promoter; research clinical testing; response; sickling; therapeutic target

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.

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。患者具有慢性致残性发病率和早期死亡率。胎儿血红蛋白（HbF：a2，g2）是正常存在于所有人类中的另一种内源性血红蛋白，但通常在婴儿期被抑制到低水平。胎儿血红蛋白的药理学增加被确立为有效的治疗策略，因为数十年的研究表明，HbF和F细胞的任何增量增加都会降低镰状细胞病或b-地中海贫血的严重性。羟基脲（HU）是FDA批准的唯一用于治疗镰状细胞病的药物，其有益效果主要是由于其增加HbF的能力，并非所有患者都有良好的反应。其他疗法可以单独使用或与HU联合使用，将有助于解决严重未满足的医疗需求。在评价珠蛋白疾病的新疗法中的一个混杂问题是患者的基础HbF水平的广泛变异性，其与改变基线HbF水平并影响治疗反应的不同基因修饰剂谱相关。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，我们在报告基因测定中发现了以前未被识别的、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。该建议是确定三种治疗候选物中的哪一种在从具有不同遗传修饰剂谱和基线HbF水平的基因分型的镰状细胞患者培养的红系细胞中最有效，以便选择用于临床试验中评估的最佳药剂。我们的目标包括：目标一：确定3种候选治疗剂在来自具有不同遗传修饰剂谱和HbF水平的基因分型镰状细胞患者的红系祖细胞中的比较体外活性，并选择用于临床的最佳药物。 试验目的II：开发一种最有效的治疗药物制剂，用于在患者人群中进行临床试验的快速评估 公共卫生关系：该提案将评估3种安全的口服治疗药物在血红蛋白疾病、导致终身发病率和早期死亡率的严重血液病、美国每年超过10亿美元的医疗负担和国际儿童高死亡率中的新医疗用途。候选疗法已经被批准用于其他医疗条件或后期测试。在完成对培养的患者细胞的拟议研究后，可以在患者群体中测试最有效的药剂，并且可以方便地将新疗法应用于他们的医疗护理。