in vivo Studies of Clinical Stage Globin Modulators

临床阶段珠蛋白调节剂的体内研究

基本信息

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
项目类别：
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

项目摘要

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）：遗传性疾病，可减少血红蛋白A 2链的产量或改变结构（2-甲性疾病或镰状细胞疾病）是世界上最常见的单基因疾病之一，遭受了全球数百万的折磨，并被WHO为全球健康负担指定。胎儿血红蛋白（HBF：12，32）是所有人类中存在的另一种类型的血红蛋白，但通常在婴儿期被抑制至低于2％的水平。数十年的生化，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疾病的严重程度，或者降低了2-甲性疾病的威胁生命的贫血。胎儿血红蛋白（3-珠蛋白链）生产的药理增强，以取代有缺陷或缺失的2-珠链链，以治疗方式确定。不同化学类别的一小部分治疗剂可以通过实验诱导HBF，其中一些已在临床上进行了测试。证明可以诱导HBF的镰状细胞疾病和β-核阿无血症的药物包括：细胞毒性化学治疗剂（例如羟基脲（HU），5-氮杂替丁蛋白和德替啶），短链脂肪酸（SCFAS）和衍生物（SCFADS）（SCFADS）（SCFADS），以及某些HDAC Indibitors。有些人在减少住院和输血依赖性方面显示了原则证明，但是除了HU以外，需要肠胃外给药或大剂量，或者是细胞毒性和诱变，并且没有证明适合广泛应用。此外，任何新的化学实体都需要昂贵的毒理学和开发成本来批准FDA。我们最近开发并利用了一种新型的高通量筛查程序来询问已经在其他条件下批准了FDA批准的药物库，并确定了一些新颖的小组，并且以前未被认可的有效HBF诱导的药物有些具有良性安全性。该活性在次要基因测定，红细胞培养和狒狒的试点研究中得到了验证。该提议是为了确认和比较3种候选HBF诱导剂在非人类灵长类动物模型中的功效，该模型已预测了随后对其他药物的人类反应。这将允许选择用于快速临床应用的治疗性。我们的目的包括：目标I：确定在贫血非人类灵长类动物中候选疗法的比较体内活性。 AIM II：准备选定治疗的药物配方公共卫生相关性：该提案将评估三种治疗剂，用于模拟镰状细胞疾病和β地中海贫血的动物模型中的新医疗用途，全世界严重的血液疾病。治疗药已被批准用于其他情况。拟议的研究完成后，可以在患者人群中测试最有效的药物，并且可以快速应用新的疗法。