Hepcidin therapy for iron overload and hematologic disorders

描述（由申请人提供）：铁超负荷是遗传性血色病、2-地中海贫血和需要长期输血的各种贫血的发病率和死亡率的主要原因。目前铁超载治疗的替代方案是一个高度优先事项，反映在最近的NIH倡议（PAS-10-046）。铁调素缺乏症是几乎所有遗传性血色病患者铁超载的直接原因，地中海贫血中间型，并可能导致铁超载和分布不均？重型地中海贫血铁调素治疗是预防和治疗这些疾病中铁过载的合理实验方法。天然hepcidin是昂贵的，快速从循环中清除，并且不能口服吸收。我们开发了7-9个氨基酸的肽，“minihepcidins”，其模拟hepcidin的活性并超过其效力。一些已经被设计用于口服吸收，并且通过小鼠口服途径显示出相当大的活性。我们将确定minihepcidins预防铁过载或逆转其在血色病和？地中海贫血，并检查hepcidin激动剂对？在小鼠模型和骨髓培养物中观察地中海贫血症红细胞生成，并确定可以改善贫血的机制。具体来说，我们将：1。根据C57 BL/6小鼠和铁调素基因敲除小鼠的剂量-反应关系和低铁作用持续时间，选择胃肠外和口服minihepcidin进行后续研究。2.确定微型铁调素在遗传性血色病动物模型中的作用。a.在重度（hepcidin基因敲除）或中度（HFE基因敲除）遗传性血色病小鼠模型中，断奶后开始使用minihepcidin能否预防铁过载的发生？B. minihepcidin治疗铁过载（hepcidin或HFE敲除）小鼠是否可以将铁从脆弱的细胞和组织（肝细胞，胰岛细胞，心肌细胞）重新分配到相对耐铁的巨噬细胞？C. minihepcidins能逆转铁诱导的肝硬化沙土鼠模型中铁超负荷相关的肝损伤吗？3.确定minihepcidins在？动物模型中的作用-地中海贫血a. minihepcidins可以预防小鼠模型中的铁过载吗？-地中海贫血中间，而改善（或不恶化）贫血？B. minihepcidins能改善输血小鼠的铁超载吗？-重型地中海贫血和重新分配铁到不太脆弱的位置，而不会恶化贫血？C.确定minihepcidins可以改善的机制？地中海贫血性红细胞生成该项目将确定minihepcidins作为进一步开发的可行药物，并最终通过为铁过载疾病患者提供改进的治疗选择来帮助他们。 公共卫生相关性：铁超载疾病是一个重要的医疗问题，需要新的治疗方法。在对铁代谢了解的最新进展的基础上，我们建议开发和测试新型药物来治疗遗传性血色病和库利贫血中的铁超载。

DESCRIPTION (provided by applicant): Iron overload is the main cause of morbidity and mortality in hereditary hemochromatosis, 2-thalassemia and various anemias that require chronic transfusions. Alternatives to current treatments of iron overload are a high priority, as reflected in a recent NIH initiative (PAS-10-046). Hepcidin deficiency is the direct cause of iron overload in nearly all cases of hereditary hemochromatosis and in ?-thalassemia intermedia, and may contribute to iron overload and maldistribution in ?-thalassemia major. Hepcidin therapy is a rational experimental approach to the prevention and treatment of iron overload in these disorders. Natural hepcidin is expensive, rapidly cleared from circulation and not orally absorbable. We developed 7-9 amino acid peptides, "minihepcidins" that mimic the activity of hepcidin and exceed its potency. Some have been engineered for oral absorption, and have shown considerable activity by oral route in mice. We will determine the potential of minihepcidins to prevent iron overload or reverse its toxic effects in hemochromatosis and ?-thalassemia, and examine the effects of hepcidin agonists on ?-thalassemic erythropoiesis in mouse models and in bone marrow cultures and identify those mechanisms that could ameliorate anemia. Specifically, we will: 1. Select a parenteral and an oral minihepcidin for subsequent studies based on the dose-response relationship and duration of hypoferremic effect in C57BL/6 mice and hepcidin knockout mice. 2. Define the effects of minihepcidins in animal models of hereditary hemochromatosis. a. Can minihepcidins started after weaning prevent the development of iron overload in mouse models of severe (hepcidin knockout) or moderate (HFE knockout) hereditary hemochromatosis? b. Can minihepcidin treatment of mice with established iron overload (hepcidin or HFE knockouts) redistribute iron away from vulnerable cells and tissues (hepatocytes, pancreatic islet cells, cardiomyocytes) to relatively iron-resistant macrophages? c. Can minihepcidins reverse iron overload-related liver damage in the gerbil model of iron-induced hepatic cirrhosis? 3. Define the effects of minihepcidins in animal models of ?-thalassemia. a. Can minihepcidins prevent iron overload in a mouse model of ?-thalassemia intermedia, while improving (or not worsening) anemia? b. Can minihepcidins ameliorate iron overload in transfused mice with ?-thalassemia major and redistribute iron to less vulnerable locations, without worsening anemia? c. Identify mechanisms by which minihepcidins can improve ?-thalassemic erythropoiesis. This project would establish minihepcidins as viable drug leads for further development, and would eventually help patients with iron overload disorders by providing them with improved therapeutic options. PUBLIC HEALTH RELEVANCE: Iron overload diseases are an important medical problem in need of new treatments. Building on recent advances in the understanding of iron metabolism, we propose to develop and test new kinds of medications for the treatment of iron overload in hereditary hemochromatosis and Cooley's anemia.