in vivo Studies of Clinical Stage Globin Modulators

描述（由申请人提供）：减少血红蛋白A 2链产生或改变结构的遗传性疾病（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，折磨着全世界数百万人，并被世卫组织指定为全球健康负担。胎儿血红蛋白（HbF: 12,32）是另一种存在于所有人类中的血红蛋白，但通常在婴儿期被抑制到2%以下。数十年的生化、临床和流行病学研究表明，HbF的任何增加都会降低镰状细胞病的严重程度，或降低危及生命的2-地中海贫血。增加胎儿血红蛋白（3-珠蛋白链）的产生，以取代有缺陷或缺失的2-珠蛋白链，已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中诱导HbF，其中一些已经进行了临床试验。在镰状细胞病和地中海贫血中诱导HbF的药物类别包括：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。一些已显示出减少住院和输血依赖的原理证明，但是，除了HU，需要肠外给药或大剂量，或具有细胞毒性和诱变性，并没有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FDA批准的开发成本。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获得fda批准用于其他条件的药物化学库，并确定了一组新的，以前未被识别的强效hbf诱导药物，其中一些具有良好的安全性。该活性在二级基因分析、红细胞培养和狒狒的初步研究中得到验证。本研究旨在证实并比较3种候选hbf诱导剂在非人灵长类动物模型中的疗效，该模型已被用于预测人类对其他药物的后续反应。这将允许选择治疗快速临床应用。我们的目标包括：目的一：确定候选疗法在贫血非人灵长类动物体内的相对活性。目的二：制备所选治疗药物的制剂

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.