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 贫血影响了约25％的世界人口，并导致不利结果。几种贫血形式， 包括炎症贫血（AI）和铁缺乏铁缺乏贫血（IRIDA），部分原因是 病理铁（FE）限制。在这种情况下，慢性免疫激活或遗传突变上调 Fe登记的马龙肝素，进而抑制了唯一已知的FE出口商铁杆菌的活性。 因此，肝素超过了通过血红蛋白回收释放的FE释放的严重形式的低铁血症 巨噬细胞，肠球菌吸收的营养铁和其他储存的FE不能导出到等离子体 铁载体蛋白转铁蛋白用于分布。 超过肝素患者的FE替代可能会受到挑战。最静脉注射替代药物 是在巨噬细胞中积累和代谢的Fe-碳水化合物纳米颗粒，需要铁托蛋白 用于动员。那就是静脉替代物可以简单地对贫血校正具有有限的效率 有可能导致巨噬细胞中的FE超负荷。肝素驱动的FE限制也限制了 营养费补充剂。没有临床可用的肝素调节药物。促红细胞生成刺激 特工（ESA）可能为某些患者提供治疗益处，但与心血管毒性有关， 在某些研究中，血栓形成和恶性肿瘤。 另一种方法是通过独立于铁蛋白的机制将FE直接传递到转铁蛋白。 静脉注射配方奶粉，含有柠檬酸铁（FPC），将Fe直接释放至转铁蛋白 FDA批准在血液透析过程中使用。但是，必须注意确保血清FPC 浓度不超过血清总Fe结合能力，因为暴露于有毒不稳定的Fe之上 临界点。为了安全地管理有意义的FE数量，FPC在数小时内慢慢注入。 仍然需要药物有效，安全地通过非洲铁蛋白而独立地复制Fe的需求 途径。我们指出，可以通过 协调化学校长的明智应用。在这里，我们建议基于集合的药物设计 前瞻性定义的分子特性。以支持我们方法的初步体外和体内数据是 我们使用复杂的Fe-BBG（BBG = N，N-（BIS）-2-羟基苯基L-谷氨酸）提供了我们合成为 我们最初的药物原型。我们将迭代合成并筛选一个复合物库，以便于安全和安全 信号。有前途的候选人将提出提升的候选人，以证明Anemoni校正的热效率 irida和慢性肾脏疾病的啮齿动物模型。这项工作的输出将是一种或多种风险 候选人作为直接转移的Fe替代药物。