Hepcidin therapy for iron overload and hematologic disorders

描述(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主要致病和死亡原因。目前铁超载治疗的替代方案是一个高度优先的问题，这反映在美国国立卫生研究院最近的一项倡议(PAS-10-046)中。海普西丁缺乏是几乎所有遗传性血色素沉着症和中间地中海贫血患者铁超载的直接原因，也可能是重型地中海贫血铁超载和分布不均的原因。海普西丁治疗是预防和治疗这些疾病中铁超载的合理的实验方法。天然的海普西丁价格昂贵，很快就会从循环中清除，而且不能被口服吸收。我们开发出了7-9个氨基酸的多肽，即“迷你海普西丁”，它模仿海普西丁的活性，并超过了它的效力。一些已经被设计用于口服吸收，并在小鼠的口服途径中显示出相当大的活性。我们将在血色素沉着症和β-地中海贫血中确定小肝素预防铁超载或逆转其毒性作用的潜力，并在小鼠模型和骨髓培养中检测小肝素激动剂对β-地中海贫血的影响，并确定那些可以改善贫血的机制。具体来说，我们将：1.根据C57BL/6小鼠和小鼠去铁基因敲除小鼠的剂量-反应关系和低铁效应持续时间，选择一种注射用的和一种口服的米非西丁进行后续研究。2.明确小分子肝素在遗传性血色病动物模型中的作用。A.在断奶后开始使用MINIPSIDINS能否防止重度(HFE基因敲除)或中度(HFE基因敲除)遗传性血色素沉着症小鼠模型铁超载的发生？小鼠铁超载(海普西丁或HFe基因敲除)的治疗能否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？在铁诱导的肝硬变沙土鼠模型中，MINHIPDINS能否逆转铁超载相关的肝损伤？3.确定MINEPIDINS在β-地中海贫血动物模型中的作用。在改善(或不恶化)贫血的同时，小型海藻毒素能否预防中间地中海贫血小鼠模型的铁负荷过高？B.小肝素能否改善患有重型地中海贫血的输血小鼠的铁负荷，并将铁重新分配到不那么脆弱的部位，而不会恶化贫血？C.确定MINHEPIDINS可改善地中海贫血红细胞生成的机制。该项目将建立MINHEPIDINS作为进一步开发的可行药物线索，并最终通过为铁超负荷障碍患者提供更好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学问题，需要新的治疗方法。在了解铁代谢的最新进展的基础上，我们建议开发和测试治疗遗传性血色素沉着症和库利氏贫血中铁超载的新药物。

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.