Hepcidin Replacement Therapy for Iron Overload Disorders

描述（由申请人提供）：铁超负荷疾病，包括遗传性血色病，通常是隐性的，在临床症状出现之前会引起进行性的，有时是不可逆的终末器官损伤。重要器官中的铁过载增加了肝病（肝硬化、癌症）、心脏病发作或心力衰竭、糖尿病、骨关节炎、骨质疏松症、代谢综合征和其他疾病的风险。铁超载可以通过接受大量输血或消耗高水平的补充铁来遗传或获得。在其他方面健康的人的常规治疗包括定期抽血或铁螯合剂，如去铁胺。大多数类型的铁过载与低水平的铁调素有关，铁调素是一种通过触发膜铁转运蛋白（ferroportin）降解来调节铁代谢的肽，膜铁转运蛋白是一种定位于吸收性肠细胞以及肝细胞和巨噬细胞上的铁转运蛋白。最近，已报道铁调素激动剂降低小鼠中的血清铁水平（Nemeth和Ganz，2011）。然而，由于生产困难和血浆半衰期短，铁调素本身作为治疗剂是有问题的。含有天然铁调素的铁转运蛋白结合残基的肽（称为迷你铁调素）更容易产生。虽然迷你铁调素在体外和体内显示铁调素活性，但它们对铁转运蛋白的亲和力落后于天然铁调素的亲和力一个对数或更多（Preza，2011）。我们建议开发一个最好的类hepcidin融合蛋白含有人Fc。预期铁调素-Fc具有等于或优于铁调素的活性，并且具有有利的药代动力学，血浆半衰期增加，允许每月一次给药。

DESCRIPTION (provided by applicant): Iron-overload disorders, including hereditary hemochromatosis, are typically insidious, causing progressive and sometimes irreversible end-organ injury before clinical symptoms develop. Iron overload in vital organs increases the risk for liver disease (cirrhosis, cancer), heart attack or heart failure, diabetes mellitus, osteoarthrtis, osteoporosis, metabolic syndrome, and other disorders. Iron overload can be inherited or acquired by receiving numerous blood transfusions or consuming high levels of supplemental iron. Routine treatment in an otherwise-healthy person consists of regularly scheduled phlebotomies or iron-chelating agents like deferoxamine. Most types of iron overload are associated with low levels of hepcidin, a peptide that regulates iron metabolism by triggering degradation of ferroportin, an iron-transport protein localized on absorptive enterocytes as well as hepatocytes and macrophages. Recently, hepcidin agonists have been reported to reduce serum iron levels in mice (Nemeth and Ganz, 2011). However, hepcidin itself is problematic as a therapeutic because of difficulties in production and short plasma half-life. Peptides (termed minihepcidins) containing the ferroportin-binding residues of native hepcidin are more easily produced. While minihepcidins show hepcidin activity in vitro and in vivo, their affinity for ferroportin lags behind that of native hepcidin by a log or more (Preza, 2011). We propose to develop a best-in-class hepcidin fusion protein containing the human Fc. Hepcidin-Fc is expected to have activity equal to or better than hepcidin and have favorable pharmacokinetics with increased plasma half-life permitting once monthly administration.