Development of a clinical hemoglobin modulator

临床血红蛋白调节剂的开发

• 批准号: 8782071
• 负责人: SUSAN Park PERRINE
• 金额: $ 50万
• 依托单位: PHOENICIA BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8782071
• 关键词: Adolescent; Adult; Affect; Amino Acids; Anemia; Benign; Benserazide; Biochemical; Biological Assay; Canada; Cells; Chemicals; Chronic; Clinical; Clinical Protocols; Clinical Trials; Complex; Conduct Clinical Trials; Country; Development; Disease; Dose; Drug Design; Drug Formulations; Enhancers; Epidemiologic Studies; Erythroid; Erythroid Cells; Europe; FDA approved; Fetal Hemoglobin; Genes; Genetic; Globin; Grant; Health; Hematological Disease; Hemoglobin; Hemoglobin A; Hemoglobinopathies; Hemolytic Anemia; Hospitalization; Human; Lead; Levodopa; Libraries; Life; Medical; Modality; Modeling; Mutation; Neurologic; Oral; Organ; Papio; Parkinson Disease; Patients; Pharmaceutical Preparations; Phase; Primates; Production; Regimen; Reporter; Research; Safety; Severities; Sickle Cell Anemia; Small Business Technology Transfer Research; Structure; Syndrome; Tablets; Testing; Thalassemia; Therapeutic; Therapeutic Agents; Toxicology; Transfusion; Work; beta Thalassemia; cost; fetal globin; global health; high throughput screening; hydroxyurea; in vivo; infancy; mortality; nonhuman primate; novel; older patient; pre-clinical; progenitor; programs; promoter; response; sickling; success; therapeutic target

DESCRIPTION (provided by applicant): The ¿-thalassemias and sickle cell disease are serious genetic blood diseases, which are WHO- designated as a growing global health burden. The disorders decrease production or alter structure of the b-chain of adult hemoglobin A and are characterized by anemia, chronic organ damage, and early mortality. HbF is another type of normal hemoglobin which is suppressed in infancy. Decades of research have shown that any incremental increase in HbF reduces the severity of sickle cell disease and the life-threatening anemia of b-thalassemia. Pharmacologic augmentation of fetal hemoglobin (g-globin chain) production, to replace the defective or missing b-globin chains, is accepted as a therapeutic modality. Only one therapeutic, hydroxyurea, is approved for sickle cell disease, and no definitive therapeutic agent is approved for beta thalassemia. Additional HbF- inducing therapies are needed. We utilized a novel high-throughput screening program to interrogate a library of drugs which are already EMEA or FDA-approved for other medical conditions, and identified a panel of previously unrecognized potent HbF-inducing drugs. HbF-inducing activity was validated in a secondary reporter assays, in patients' erythroid progenitors, and 3 lead therapeutics were evaluated in baboons on our Phase I STTR grant. This primate model has been predictive of subsequent human responses for other drugs. One therapeutic, Benserazide, was particularly intriguing in inducing high-level fetal globin, by 33-fold over baseline, with brif treatment in the baboon. We found the drug suppresses two components of a major repressor complex of the fetal hemoglobin gene. The drug has been used for 3 decades in Europe and Canada as a PK enhancer of levodopa for treatment of Parkinson's disease, and has a benign safety profile. Accordingly, we propose to repurpose Benserazide for treatment the beta hemoglobinopathies. Our Aims include: Aim I: Determine an optimal dosing regimen of Benserazide for inducing sustained HbF in vivo in anemic nonhuman primates Aim II: Produce a formulation suitable for a dose-ranging trial in hemoglobinopathy patients Aim III: Obtain a US IND to evaluate the EU-approved therapeutic in patients with sickle cell disease and beta thalassemia

描述（由申请人提供）：地中海贫血和镰状细胞病是严重的遗传性血液病，被WHO指定为日益严重的全球健康负担。这些疾病减少成人血红蛋白A的b链的产生或改变其结构，并以贫血、慢性器官损伤和早期死亡为特征。HbF是另一种在婴儿期受到抑制的正常血红蛋白。数十年的研究表明，HbF的任何增量增加都会降低镰状细胞病和危及生命的b-地中海贫血贫血的严重程度。药理学增加胎儿血红蛋白（g-珠蛋白链）的生产，以取代缺陷或缺失的b-珠蛋白链，被认为是一种治疗方式。只有一种治疗药物，羟基脲，被批准用于镰状细胞病，没有明确的治疗药物被批准用于β地中海贫血。需要额外的HbF诱导疗法。我们利用一种新型的高通量筛选程序来询问已经获得EMEA或FDA批准用于其他疾病的药物库，并确定了一组以前未被认识到的强效HbF诱导药物。在患者红系祖细胞中的二级报告基因测定中验证了HbF诱导活性，并在我们的I期STTR资助中在狒狒中评价了3种先导疗法。这种灵长类动物模型已经预测了随后人类对其他药物的反应。一种治疗剂，苄丝肼，在诱导高水平的胎儿珠蛋白方面特别有趣，超过基线33倍，在狒狒中进行brif治疗。我们发现该药物抑制胎儿血红蛋白基因主要阻遏复合物的两种成分。该药物已在欧洲和加拿大作为左旋多巴的PK增强剂用于治疗帕金森病已有30年，并且具有良好的安全性。因此，我们建议将苄丝肼重新用于治疗β血红蛋白病。我们的目标包括：目标一：确定苄丝肼在贫血非人灵长类动物体内诱导持续HbF的最佳给药方案目标II：生产适用于血红蛋白病患者剂量范围试验的制剂目标III：获得美国IND，以评估欧盟批准的治疗镰状细胞病和β地中海贫血患者的治疗方法