Development of a clinical hemoglobin modulator

临床血红蛋白调节剂的开发

基本信息

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
项目类别：
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

项目摘要

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疾病，被世界卫生组织指定为日益严重的全球健康负担。这些疾病减少了成人血红蛋白 A 的 B 链的产生或改变了结构，其特点是贫血、慢性器官损伤、 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 的任何增加都会降低镰状细胞病和危及生命的贫血的严重程度。 b-地中海贫血。药物增加胎儿血红蛋白（g-珠蛋白链）的产生，以替代有缺陷或缺失的 b-珠蛋白链，被认为是一种治疗方法，即羟基脲，被批准用于治疗镰状细胞病。 β 地中海贫血的最终治疗药物被批准，我们还需要额外的 HbF 诱导疗法来研究已获得 EMEA 或 FDA 批准的药物库。其他医疗状况，并确定了一组先前未被识别的有效 HbF 诱导药物，并在患者的红细胞祖细胞中进行了二次报告分析，并在我们的第一阶段 STTR 资助中对狒狒进行了 3 种主要治疗药物的评估。这种灵长类动物模型可以预测人类对其他药物的后续反应，一种治疗剂苄丝肼在诱导高水平胎儿珠蛋白方面特别令人感兴趣，其水平是基线的 33 倍。通过对狒狒进行快速治疗，我们发现该药物可抑制胎儿血红蛋白基因的主要阻遏复合物的两种成分。该药物在欧洲和加拿大已作为左旋多巴的 PK 增强剂用于治疗帕金森病。因此，我们建议重新利用苄丝肼来治疗 β 血红蛋白病。目标 I：确定最佳给药方案。苄丝肼在贫血非人灵长类动物体内诱导持续 HbF 目标 II：生产适合血红蛋白病患者剂量范围试验的制剂目标 III：获得美国 IND 来评估欧盟批准的镰状细胞病和β细胞病患者治疗方法地中海贫血