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.

项目概要/摘要 贫血症影响着世界约 25% 的人口，并导致不良后果。几种形式的贫血， 包括炎症性贫血（AI）和难治性缺铁性贫血（IRIDA），部分原因是 病理性铁（Fe）限制。在这些情况下，慢性免疫激活或基因突变上调 铁调节激素铁调素，反过来又抑制铁转运蛋白（唯一已知的铁输出蛋白）的活性。 因此，铁调素过量会导致严重的低铁血症，因为铁通过血红蛋白循环释放出来。 巨噬细胞、肠上皮细胞吸收的营养铁和其他储存的铁不能输出到血浆 用于分配的铁载体蛋白转铁蛋白。 铁调素过量患者的铁替代可能具有挑战性。大多数静脉铁替代药物 是铁碳水化合物纳米颗粒，在巨噬细胞中积累和代谢，需要铁转运蛋白 用于铁的动员。因此，静脉注射替代疗法对于纠正贫血的功效同时有限，而 可能导致巨噬细胞铁过载。铁调素驱动的铁限制也限制了 营养铁补充剂。临床上尚无可用的铁调素调节药物。刺激红细胞生成 药物（ESA）可能为某些患者提供治疗益处，但与心血管毒性相关， 一些研究显示血栓形成和恶性肿瘤。 另一种方法是通过独立于铁转运蛋白的机制将铁直接递送至转铁蛋白。一个 包含焦磷酸柠檬酸铁 (FPC) 的静脉制剂，可直接将 Fe 释放至转铁蛋白 FDA 批准在血液透析期间使用。然而，必须注意确保血清FPC 浓度不超过血清总铁结合能力，因为高于此值时会暴露于有毒的不稳定铁 临界点。为了安全地施用具有治疗意义的量的铁，需要在数小时内缓慢注入 FPC。 对于通过不依赖铁转运蛋白来有效、安全地补充铁的药物的需求仍然未得到满足 途径。我们认为可以通过以下方式开发一种高效的直接转铁蛋白铁替代药物 配位化学原理的明智应用。在这里，我们提出基于一组的药物设计 前瞻性定义的分子特性。支持我们方法的初步体外和体内数据是 使用我们合成的复合物 Fe-BBG（BBG = N,N-（双）-2-羟基苄基-L-谷氨酸）提供 我们最初的药物原型。我们将迭代合成和筛选复合物库，以确保其功效和安全性 信号。有前途的候选者将被推进以证明对 anemai 矫正的治疗功效 IRIDA 和慢性肾病的啮齿动物模型。这项工作的输出将被一个或多个去风险 开发作为直接转铁蛋白铁替代药物的候选药物。