Preclinical Development of a New Drug for Treating Anemia of Chronic Inflammation

描述(由申请人提供)：开发与慢性疾病状态相关的贫血的新治疗方法存在着强烈的未得到满足的需求，统称为慢性炎症贫血(ACI)。ACI在美国非常流行，对公众的发病率和死亡率有很大贡献。尽管每年花费数十亿美元治疗 对于ACI患者，目前的治疗方法在许多患者中缺乏疗效，并可能导致严重的不良反应。ACI的机制涉及炎性细胞因子抑制红细胞的骨髓生成，主要通过两条相互依赖的途径：(1)阻止巨噬细胞向红系前体细胞的铁转移(铁限制)和(2)直接作用于 红系前体传递抑制信号。铁限制有效地使红系变得敏感 祖细胞对炎性细胞因子的直接抑制作用。临床上，大剂量静脉输铁可以改善ACI患者的贫血。我们正在开发一种安全有效的治疗方法来纠正这些患者的贫血，基于我们的发现，乌头酸酶产物，即异柠檬酸，作为第二信使调节铁的信号来刺激红细胞生成。我们通过在体外向红系祖细胞提供外源性异柠檬酸，取消了铁限制的抑制作用，恢复了对炎性细胞因子的抵抗，从而建立了临床应用。为了确定临床可行性和商业潜力，我们建议在ACI的主要动物模型-实验诱导的慢性自身免疫性关节炎的大鼠-中研究异柠檬酸的作用。我们的目标是通过以下方式为我们的新型异柠檬酸盐技术进行概念验证：(1)根据预期的临床用药方案，证明异柠檬酸在ACI大鼠中的疗效；(2)测量异柠檬酸治疗对红细胞生成功能生物标记物的生理影响，以证明异柠檬酸是有效的；(3)测量血清生物标记物，并评估尸检器官的全身毒性迹象，以证明异柠檬酸是安全的。等柠檬酸技术是由弗吉尼亚大学发明的。科学研究人员/发明人与坎伯兰制药公司及其附属公司合作，正在开发异柠檬酸盐作为一种用于静脉注射或口服剂型的新药，以纠正急性脑梗塞患者的贫血。 公共卫生相关性：数百万患有终生疾病的人，例如涉及肾脏或癌症的人也患有贫血。目前这种类型的贫血(称为慢性炎症贫血)的治疗方法风险大、费用高，而且对某些患者群体无效。在拟议的研究中，我们将研究一种治疗慢性炎症贫血的新药候选药物，并在与人类疾病相关的动物模型中证明它是安全有效的。

DESCRIPTION (provided by applicant): A strong unmet need exists to develop new treatments for anemias associated with chronic disease states, collectively referred to as anemia of chronic inflammation (ACI). ACI is highly prevalent in the U.S. and makes a large contribution to public morbidity and mortality. Despite billions of dollars spent annually to treat ACI patients, current therapies lack efficacy in many patients and cause potentially serious adverse effects. The mechanism for ACI involves inflammatory cytokines acting to inhibit marrow production of red cells, primarily by two interdependent pathways: (1) blocking iron transfer from macrophages to erythroid precursors (iron restriction) and (2) acting directly on the erythroid precursors to transmit inhibitory signals. Iron restriction potently sensitizes erythroid progenitors to the direct inhibitory effects of the inflammatory cytokines. Clinically, high-dose intravenous iron infusions can ameliorate anemia in ACI patients. We are developing a safe and efficacious therapy to correct anemia in these patients based on our discovery that the aconitase enzyme product, namely isocitrate, functions as a second messenger mediating iron's signal to stimulate erythropoiesis. We established the clinical utility by showing that exogenous isocitrate provided to erythroid progenitors in vitro abrogates the inhibitory effects of iron restriction and restores resistance to inflammatory cytokines. To establish clinical feasibility an commercial potential, we propose to study isocitrate's effects in the principal animal model for ACI, rats with experimentally induced chronic autoimmune arthritis. We aim to demonstrate proof-of-concept for our novel isocitrate technology by: (1) demonstrating isocitrate's curative efficacy in ACI rats using a dosing regimen per intended clinical use; (2) measuring physiological effects of isocitrate therapy on functional biomarkers of erythropoiesis to demonstrate isocitrate is effective; and (3) measuring serum biomarkers and assessing organs at necropsy for signs of systemic toxicity to demonstrate isocitrate is safe. The isocitrate technology was invented at the University of Virginia. The scientific investigators/inventors, in collaboration with Cumberland Pharmaceuticals Inc. and affiliates, are developing isocitrate as a new drug product for intravenous injection or oral dosage form to correct anemia in ACI patients. PUBLIC HEALTH RELEVANCE: Millions of people with lifelong diseases, for example those involving the kidney or cancers also have anemia. Current treatments for this type of anemia (known as anemia of chronic inflammation) are risky, expensive, and ineffective for some patient populations. In the proposed studies, we will study a new drug candidate for anemia of chronic inflammation and demonstrate that it safe and effective in an animal model relevant to the human disease.