in vivo Studies of Clinical Stage Globin Modulators

临床阶段珠蛋白调节剂的体内研究

• 批准号: 8202990
• 负责人: SUSAN Park PERRINE
• 金额: $ 30.43万
• 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 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8202990
• 关键词: Adult; Affect; Anemia; Animal Model; Azacitidine; Benign; Biochemical; Biological Assay; Cell Culture Techniques; Chemicals; Clinical; Decitabine; Dependency; Development; Disease; Dose; Drug Formulations; Epidemiologic Studies; Erythroid Cells; FDA approved; Fetal Hemoglobin; Genes; Globin; Hematological Disease; Hemoglobin; Hemoglobin A; Hereditary Disease; Histone Deacetylase Inhibitor; Hospitalization; Human; Inborn Genetic Diseases; Libraries; Life; Medical; Modality; Modeling; Mutation; Oral; Papio; Patient Care; Pharmaceutical Preparations; Pilot Projects; Production; Reporter; Safety; Severities; Sickle Cell; Sickle Cell Anemia; Simulate; Staging; Structure; Syndrome; Testing; Thalassemia; Therapeutic; Therapeutic Agents; Toxicology; Transfusion; Volatile Fatty Acids; beta Thalassemia; chemotherapeutic agent; clinical application; comparative; comparative efficacy; cost; cytotoxic; fetal globin; global health; high throughput screening; hydroxyurea; in vivo; infancy; nonhuman primate; novel; patient population; pre-clinical; programs; promoter; response; safety testing; sickling; small molecule libraries; success; therapeutic target

DESCRIPTION (provided by applicant): Inherited disorders which decrease production or alter structure of the 2-chain of hemoglobin A (2-thalassemias or sickle cell disease) are among the most common monogenic diseases in the world, afflicting millions worldwide, and are designated by WHO as a global health burden. Fetal hemoglobin (HbF: 12, 32) is another type of hemoglobin which is present in all humans, but is normally suppressed in infancy to levels below 2%. Decades of biochemical, clinical, and epidemiologic research have shown that any incremental increase in HbF reduces the severity of sickle cell disease, or reduces the life-threatening anemia of 2-thalassemia. Pharmacologic augmentation of fetal hemoglobin (3-globin chain) production, to replace the defective or missing 2-globin chains, is established as a therapeutic modality. A small panel of therapeutic agents of different chemical classes can induce HbF experimentally, and a few have been tested clinically. Classes of agents shown to induce HbF in sickle cell disease and beta-thalassemia include: cytotoxic chemotherapeutic agents (such as hydroxyurea (HU), 5-azacytidine, and decitabine), short chain fatty acids (SCFAs) and derivatives (SCFADs), and some HDAC inhibitors. Some have shown proof-of-principle in reducing hospitalizations and transfusion dependency, but, except for HU, require parenteral administration or large doses, or are cytotoxic and mutagenic, and have not proven suitable for broad application. Further, any new chemical entities require costly toxicology and development costs for FDA approval. We recently developed and utilized a novel high-throughput screening program to interrogate a chemical library of drugs which are already FDA-approved for other conditions, and identified a select panel of novel, and previously unrecognized potent HbF-inducing drugs some of which have benign safety profiles. The activity was validated in a secondary gene assays, erythroid cell culture, and in a pilot study in baboons. This proposal is to confirm and compare the efficacy of 3 candidate HbF-inducers in a nonhuman primate model which has been predictive of subsequent human responses for other drugs. This will allow selection of a therapeutic for rapid clinical application. Our Aims include: Aim I: To determine comparative in vivo activity of the candidate therapeutics in anemic nonhuman primates. Aim II: To prepare a medicinal formulation of the selected therapeutic PUBLIC HEALTH RELEVANCE: This proposal will evaluate three therapeutics for a new medical use in an animal model that simulates sickle cell disease and beta thalassemia, serious blood diseases worldwide. The therapeutics are already approved for other conditions. Upon completion of the proposed studies, the most potent agent can be tested in the patient populations, and a new therapy can be rapidly applied to patient care.

描述（由申请人提供）：减少血红蛋白A的2-链产生或改变血红蛋白A的2-链结构的遗传性疾病（2-地中海贫血或镰状细胞病）是世界上最常见的单基因疾病之一，困扰着全世界数百万人，并被WHO指定为全球健康负担。胎儿血红蛋白（HbF：12，32）是存在于所有人类中的另一种血红蛋白，但通常在婴儿期被抑制至低于2%的水平。数十年的生物化学、临床和流行病学研究表明，HbF的任何增量增加都会降低镰状细胞病的严重程度，或减少危及生命的2-地中海贫血贫血。药理学增加胎儿血红蛋白（3-珠蛋白链）的生产，以取代缺陷或缺失的2-珠蛋白链，被确立为一种治疗方式。 一小组不同化学类别的治疗剂可以在实验上诱导HbF，并且一些已经在临床上进行了测试。显示在镰状细胞病和β-地中海贫血中诱导HbF的药剂类别包括：细胞毒性化疗剂（如羟基脲（HU）、5-氮杂胞苷和地西他滨）、短链脂肪酸（SCFA）和衍生物（SCFAD）以及一些HDAC抑制剂。一些药物已显示出减少住院和输血依赖性的原理证明，但除HU外，需要胃肠外给药或大剂量给药，或具有细胞毒性和致突变性，尚未证明适合广泛应用。此外，任何新的化学实体都需要昂贵的毒理学和FDA批准的开发成本。 我们最近开发并利用了一种新型高通量筛选程序来询问已经获得FDA批准用于其他疾病的化学药物库，并确定了一组精选的新型且以前未被认识到的强效HbF诱导药物，其中一些具有良好的安全性。该活性在次级基因测定、红系细胞培养和狒狒中的初步研究中得到验证。该提案旨在确认和比较3种候选HbF诱导剂在非人灵长类动物模型中的疗效，该模型可预测其他药物的后续人体反应。这将允许选择用于快速临床应用的治疗剂。我们的目的包括：目的I：确定候选治疗剂在贫血非人灵长类动物中的比较体内活性。目的II：制备所选治疗药物的药物制剂 公共卫生关系：该提案将评估三种疗法在模拟镰状细胞病和β地中海贫血（全球严重血液病）的动物模型中的新医疗用途。这种疗法已经被批准用于其他疾病。在完成拟议的研究后，可以在患者人群中测试最有效的药物，并将新的治疗方法快速应用于患者护理。