in vivo Studies of Clinical Stage Globin Modulators

描述(由申请人提供)：遗传性疾病减少生产或改变2-链血红蛋白A(2-地中海贫血或镰状细胞病)的结构，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，并被世卫组织指定为全球健康负担。胎儿血红蛋白(HBF：12，32)是另一种类型的血红蛋白，存在于所有人类中，但通常在婴儿时期被抑制到2%以下的水平。数十年的生化、临床和流行病学研究表明，HbF的任何增量增加都可以降低镰状细胞疾病的严重程度，或者减少危及生命的2-地中海贫血。药物增强胎儿血红蛋白(3-珠蛋白链)的产生，以取代缺陷或缺失的2-珠蛋白链，已被确立为一种治疗方式。一小部分不同化学类别的治疗剂可以在实验上诱导HBF，其中一些已经在临床上进行了测试。在镰状细胞病和β-地中海贫血中，可诱发HBF的药物包括：细胞毒性化疗药物(如羟基脲(HU)、5-氮胞苷和地西他滨)、短链脂肪酸(SCFAs)及其衍生物(SCFADs)和一些HDAC抑制剂。一些药物在减少住院和输血依赖方面已显示出原则上的证据，但除HU外，需要静脉给药或大剂量，或具有细胞毒性和诱变性，并未被证明适合广泛应用。此外，任何新的化学实体都需要昂贵的毒理学和开发成本才能获得FDA的批准。我们最近开发并利用了一种新的高通量筛选程序来询问已经被FDA批准用于其他条件的药物的化学库，并确定了一组新的、以前未被认识的有效的HBF诱导药物，其中一些具有良好的安全性。这种活性在次级基因分析、红系细胞培养和在狒狒身上的初步研究中得到了验证。这项建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有效性，该模型预测了后续人类对其他药物的反应。这将允许选择一种快速临床应用的治疗方法。我们的目标包括：目标I：确定候选疗法在贫血非人类灵长类动物中的体内比较活性。目的II：制备所选药物的药物制剂 与公共卫生相关：这项提案将在模拟镰状细胞疾病和贝塔地中海贫血的动物模型中评估三种新的医疗用途的疗法，这两种疾病是全球严重的血液疾病。这种疗法已经被批准用于其他疾病。在拟议的研究完成后，最有效的药物可以在患者群体中进行测试，一种新的治疗方法可以迅速应用于患者护理。

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.