Next Generation Therapeutics for Hemoglobinopathies

血红蛋白病的下一代治疗方法

基本信息

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
项目类别：
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

项目摘要

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）：镰状细胞疾病和2-甲性疾病是人类最常见的遗传性单基因疾病，包括全球重大的健康负担，每年损失美国医疗保健系统> 10亿美元。患者患有慢性致残性发病率和早期死亡率。胎儿血红蛋白（HBF：A2，G2）是通常存在于所有人类中的另一种内源性血红蛋白类型，但通常在婴儿期抑制至低水平。数十年的研究表明，HBF和F细胞的任何增量降低了镰状细胞疾病的严重程度或B- thalassmias的严重贫血，因此将胎儿血红蛋白的药理学增强作为一种有效的治疗策略确定为一种有效的治疗策略。羟基脲（HU）是用于治疗镰状细胞疾病的唯一唯一的FDA批准药物，其有益作用主要是由于其增加HBF的能力，并非所有患者都反应良好。可以单独使用或与HU结合使用的其他治疗剂将使严重的未满足医疗需求有益。评估球蛋白疾病中新疗法的一个混乱问题是患者基础HBF水平的广泛变异性，与不同的基因修饰剂谱有关，这些概念改变基线HBF水平并影响治疗反应。从分子建模研究和针对其他医疗状况的FDA批准的药物库的高通量筛查程序，我们发现了先前未识别的，高度有效的HBF诱导药物在记者基因测定中，并证实了它们在正常受试者中培养的细胞细胞中的活性。该建议是为了确定从具有不同遗传修饰剂谱和基线HBF水平的基因型镰状细胞患者培养的三种治疗候选者中的哪个最有效，以便在临床试验中选择最佳的FO评估。我们的目的包括：目标I：确定来自基因型型镰状细胞患者和具有不同遗传修饰剂谱和HBF水平的3种候选术中3种候选疗法的比较体外活性，并选择临床的最佳药物测试目标II：开发一种在患者人群的临床试验中快速评估的最活跃治疗的药物表述公共卫生相关性：该提案将评估3种安全的口服治疗剂，用于用于血红蛋白疾病的新医疗用途，严重的血液疾病，这些血液疾病赋予终生发病率和早期死亡率，每年的美国医疗保健负担> 10亿美元，以及国际上的童年死亡率较高。候选治疗药已被批准用于其他医疗状况或晚期测试。在拟议的培养患者细胞的拟议研究完成后，可以在患者人群中测试最有效的药物，并且可以将新的疗法适时应用于其医疗服务。