Hepcidin therapy for iron overload and hematologic disorders

描述（由申请人提供）：铁超载是遗传性血色素沉着症、2-地中海贫血和需要长期输血的各种贫血的发病和死亡的主要原因。替代目前铁超载的治疗方法是高度优先考虑的，正如最近的NIH倡议（PAS-10-046）所反映的那样。Hepcidin缺乏是几乎所有遗传性血色素沉着症病例中铁超载的直接原因。-地中海贫血，并可能导致铁超载和分布不均匀？地中海贫血主要。Hepcidin治疗是预防和治疗这些疾病中铁超载的一种合理的实验方法。天然肝磷脂价格昂贵，从循环中迅速清除，不能口服吸收。我们开发了7-9个氨基酸肽，“迷你hepcidins”，模仿hepcidin的活性，并超过其效力。一些已被改造为口服吸收，并在小鼠的口服途径中显示出相当大的活性。我们将确定在血色素沉着症和？-地中海贫血，并检查肝素激动剂对？-地中海贫血红细胞在小鼠模型和骨髓培养，并确定这些机制可以改善贫血。具体来说，我们将：1。根据C57BL/6小鼠和hepcidin敲除小鼠的低铁效应的剂量-反应关系和持续时间，选择注射和口服小hepcidin进行后续研究。2. 确定微型hepcidins在遗传性血色素沉着症动物模型中的作用。a.断奶后开始使用微hepcidins是否能预防重度（hepcidin敲除）或中度（HFE敲除）遗传性血色素沉着症小鼠模型中的铁过载？b.对铁超载（hepcidin或HFE敲除）的小鼠进行minihepcidin治疗能否将铁从易损细胞和组织（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中？c.在沙鼠铁致肝硬化模型中，微肝素能否逆转铁负荷相关的肝损伤？3. 确定微量抗血小板药物对地中海贫血动物模型的影响。a.在小鼠模型中，微量hepcidins能预防铁超载吗？-地中海贫血，而改善（或不恶化）贫血？b.微量hepcidins是否能改善输铁小鼠的铁负荷？在不加重贫血的情况下，将铁重新分配到不那么脆弱的地方？c.确定微小细胞因子改善的机制？-thalassemic红细胞生成。该项目将确立微型铁蛋白作为进一步开发的可行药物先导，并最终通过为铁超载疾病患者提供改进的治疗选择来帮助他们。

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.