A New Paradigm for Iron Replacement Therapy

铁替代疗法的新范例

• 批准号: 10715655
• 负责人: Eric Michael Gale
• 金额: $ 65.34万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10715655
• 关键词: Adenine; Affinity; Albumins; Anemia; Anemia due to Chronic Disorder; Autopsy; Binding; Biological Assay; Biological Availability; Blinded; Blood; Carbohydrates; Cardiovascular system; Caring; Carrier Proteins; Chelating Agents; Chemistry; Chronic; Chronic Kidney Failure; Citrates; Clinical; Clinical Chemistry; Combined Modality Therapy; Complex; DNA Sequence Alteration; Data; Development; Diphosphates; Dissociation; Dose; Drug Design; Drug Kinetics; Drug Modulation; Drug Screening; Enterocytes; Erythropoiesis; Erythropoietin; Excretory function; Exposure to; Formulation; Glutamic Acid; Hematology; Hemodialysis; Hemoglobin; Hepatocyte; Hormones; Hour; In Vitro; Intravenous; Iron; Iron Overload; Iron deficiency anemia; Kinetics; Knockout Mice; Libraries; Ligands; Macrophage; Magnetic Resonance Imaging; Malignant Neoplasms; Messenger RNA; Metabolism; Modeling; Modification; Molecular; Monitor; Mus; Nutritional; Output; Oxidation-Reduction; Pathologic; Pathology; Pathway interactions; Patients; Performance; Periodicity; Pharmaceutical Preparations; Placebos; Plasma; Population; Potentiometry; Production; Property; Recombinant Erythropoietin; Recycling; Refractory; Replacement Therapy; Risk; Rodent Model; Safety; Serum; Serum Albumin; Signal Transduction; Specificity; Sucrose; Therapeutic; Thermodynamics; Thrombosis; Tissues; Toxic effect; Transferrin; Treatment Efficacy; Up-Regulation; Work; absorption; adverse outcome; chemical synthesis; comparative efficacy; drug candidate; drug synthesis; experimental study; extracellular; hepcidin; immune activation; in vitro Assay; in vivo; iron absorption; lead candidate; metal transporting protein 1; mouse model; nanoparticle; nutritional supplementation; prospective; prototype; research clinical testing; screening; standard of care; uptake

Project Summary/ Abstract Anemia impacts ~25% of the world’s population and contributes to adverse outcomes. Several forms of anemia, including anemia of inflammation (AI) and iron-refractory iron deficiency anemia (IRIDA) are caused in part by pathologic iron (Fe) restriction. In these conditions, chronic immune activation or genetic mutations upregulate the Fe regulating hormone hepcidin, which in turn inhibits activity of ferroportin, the only known Fe exporter. Hepcidin excess thus imposes a severe form of hypoferremia as Fe liberated via hemoglobin recycling in macrophages, nutritional iron absorbed by enterocytes, and other stored Fe cannot be exported to the plasma iron-carrier protein transferrin for distribution. Fe replacement in patients with hepcidin excess can be challenging. Most intravenous Fe replacement drugs are Fe-carbohydrate nanoparticles that are accumulated and metabolized in macrophages, requiring ferroportin for Fe mobilization. Thus, iv replacement can simultaneously have limited efficacy for anemia correction while potentially contributing to Fe overload in macrophages. Hepcidin-driven Fe restriction also limits the efficacy of nutritional Fe supplements. There is no clinically available hepcidin-modulating drug. Erythropoiesis stimulating agents (ESA) may offer a therapeutic benefit for some patients, but are associated with cardiovascular toxicity, thrombosis, and malignancy in some studies. An alternate approach is to deliver Fe directly to transferrin via mechanisms independent of ferroportin. An intravenous formulation comprising iron pyrophosphate citrate (FPC) that releases Fe directly to transferrin has FDA approval for use during hemodialysis. However, care must be taken to ensure that serum FPC concentrations do not exceed serum total Fe binding capacity, as exposure to toxic labile Fe occurs above this threshold. To safely administer therapeutically meaningful quantities of Fe, FPC is slowly infused over hours. There remains an unmet need for drugs to efficiently and safely replenish Fe via ferroportin-independent pathways. We posit that a highly effective direct-to-transferrin Fe replacement drug can be developed through the judicious application of coordination chemistry principals. Here, we propose drug design based on a set prospectively defined molecular properties. Preliminary in vitro and in vivo data in support of our approach is provided using the complex Fe-BBG (BBG = N,N-(bis)-2-hydroxybenzyl-L-glutamic acid) that we synthesized as our initial drug prototype. We will iteratively synthesize and screen a library of complexes for efficacy and safety signals. Promising candidates will be advanced to demonstrate therapeutic efficacy for anemai correction in rodent models of IRIDA and chronic kidney disease. The output of this work will be one or more de-risked candidates for development as direct-to-transferrin Fe replacement drugs.

项目摘要/摘要