Hepcidin Replacement Therapy for Iron Overload Disorders

铁调素替代疗法治疗铁过载疾病

• 批准号: 8454605
• 负责人: JAMES W LARRICK
• 金额: $ 28.91万
• 依托单位: PANORAMA RESEARCH, INC.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-11 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8454605
• 关键词: Adverse effects; Affinity; Agonist; Amino Acids; Anemia; Animal Model; Animals; Binding; Blood Transfusion; Carrier Proteins; Cell membrane; Cells; Chimeric Proteins; Cirrhosis; Clinical; Data; Deferoxamine; Diabetes Mellitus; Dietary Iron; Disease; Drug Kinetics; Enterocytes; Epithelial Cells; Erythrocytes; Erythropoiesis; Extracellular Fluid; Fc domain; Half-Life; Heart; Heart failure; Hemochromatosis; Hepatocyte; Hereditary hemochromatosis; Homeostasis; Hour; Human; Immunoglobulin G; In Vitro; Inherited; Injury; Intestines; Iron; Iron Chelating Agents; Iron Overload; Length; Liver; Liver diseases; Malignant Neoplasms; Measures; Metabolic syndrome; Mus; Myocardial Infarction; N-terminal; Organ; Organism; Osteoporosis; Peptides; Persons; Phase; Plasma; Production; Recycling; Replacement Therapy; Reporting; Risk; Schedule; Serum iron level result; Symptoms; Thalassemia; Therapeutic; Time; Toxic effect; Venous blood sampling; Work; absorption; extracellular; hepcidin; in vitro activity; in vivo; iron deficiency; iron metabolism; macrophage; metal transporting protein 1; mouse model; peptide hormone; pre-clinical; public health relevance; receptor; research study; senescence

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.

描述（由申请人提供）：铁超负荷疾病，包括遗传性血色素沉着症，通常是阴险的，在临床症状发生之前会导致进行性逐渐，有时是不可逆的最终器官损伤。生命器官中的铁超负荷增加了肝病（肝硬化，癌症），心脏病发作或心力衰竭的风险，糖尿病，骨刺，骨质疏松症，骨质疏松症，代谢综合征和其他疾病。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取。在原本健康的人中进行的常规治疗包括定期安排的静脉植物或诸如脱铁胺这样的铁螯合剂。大多数类型的铁超载与低水平的肝素有关，肝素是一种肽，该肽通过触发铁托蛋白的降解来调节铁代谢，铁托蛋白是一种局部在吸收性肠细胞上的铁传输蛋白，以及肝细胞和巨噬细胞。最近，据报道，肝素激动剂可以降低小鼠的血清铁水平（Nemeth和Ganz，2011年）。但是，由于生产困难和短血浆半衰期，肝素本身作为一种治疗性是有问题的。更容易产生含有天然肝素的铁蛋白蛋白结合残基的肽（称为Minepcidins）。 Minihepcidins在体外和体内表现出肝素活性，但它们对铁蛋白的亲和力滞后于原生肝素或更多的原始肝素或更多（Preza，2011）。我们建议开发含有人FC的一流的肝素融合蛋白。 Hepcidin-FC有望具有等于或更好的活性，并且具有有利的药代动力学，并且血浆半衰期增加了一次，每月一次给药。