Phase 1 Study of Quercetin for the Treatment of Fanconi Anemia

槲皮素治疗范可尼贫血的一期研究

• 批准号: 8569567
• 负责人: PARINDA A. MEHTA
• 金额: $ 20万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-16 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8569567
• 关键词: Phase; Study; Quercetin; Treatment; Fanconi

Project Summary/Abstract Current therapies for children with Fanconi anemia (FA) and bone marrow failure, i.e. androgens or bone marrow transplantation, are associated with significant morbidity and mortality. Thus, there is clearly a need for a novel approach that has fewer and less severe side effects. Studies in both animals and humans indicate that high levels of systemic reactive-oxygen species (ROS) and increased sensitivity of hematopoietic progenitors to ROS play a key role in the pathogenesis of marrow failure in these children. Our long-term goal is to interdict the progression of marrow failure in FA and decrease the associated morbidity and mortality. The overall objective of this application, which is the next step towards attainment of our long-term goal, is to de- velop, at a phase 1 level, a novel approach to treatment of FA that is safer and more efficacious compared to existing approaches. It is our central hypothesis that treatment with the ROS scavenger quercetin will be safe, well tolerated and will modulate ROS levels in children with FA, which in turn will ameliorate or reverse their marrow failure. Our own preliminary data show that quercetin reverses the ill effects of ROS on hematopoiesis and insulin sensitivity in FA mice. Blood and bone marrow samples from children with FA showed similar re- sponses in vitro. These data strongly suggest that quercetin will be beneficial in stimulating hematopoiesis and preventing marrow failure in children with FA. Our multidisciplinary team is well prepared and will have access to sufficiently large population of children with FA. Quercetin is a naturally occurring anti-oxidant, found in the normal diet, and dietary supplements/multivitamin preparations. Most epidemiological studies have shown that in general, quercetin is well tolerated without major side effects. In this Phase 1 study, we will test the above hypothesis with the following specific aims: 1. Assess overall tolerance of long-term quercetin therapy in children with FA. Twelve children with FA will be treated with oral quercetin for a total of 4 months and fol- lowed closely for safety and feasibility of this approach. 2. Study pharmacokinetics (Pk) of quercetin in children with FA. To generate pediatric Pk data for quercetin, blood will be collected at the start and at the end of 4 months of quercetin therapy. These data will be used to optimize the dosing schedule (if required). 3. Proof-of-concept clinical studies. The impact of quercetin on ROS reduction and preservation of hematopoi- etic stem cell reserve will serve as surrogate markers for maintenance/prevention of progressive marrow fail- ure. Additionally, quercetin's effect on improving hematopoiesis (blood counts) and insulin sensitivity will be quantified. Expected outcomes include the demonstration that long-term quercetin therapy is safe, well tolerat- ed and achieves biologically relevant blood levels in patients with FA, a finding which will form the basis of subsequent efficacy studies. Expected positive impact is that success will lead to a new first line therapy for children with FA, obviating or at least delaying the need for transplant. The proposed research is innovative, in our opinion, as it incorporates ROS as a novel therapeutic target a novel, in a feasible approach for the preven- tion of marrow failure with a unique intervention of oral quercetin.

项目概要/摘要 目前针对范可尼贫血 (FA) 和骨髓衰竭儿童的治疗方法，即雄激素或 骨髓移植与显着的发病率和死亡率相关。因此，显然有一个 需要一种副作用越来越少的新方法。对动物和人类的研究 表明全身活性氧 (ROS) 水平高且造血敏感性增加 ROS 祖细胞在这些儿童骨髓衰竭的发病机制中发挥着关键作用。我们的长期目标 目的是阻止 FA 中骨髓衰竭的进展并降低相关的发病率和死亡率。这 该应用程序的总体目标是实现我们长期目标的下一步，是去 在 1 期水平上开发一种治疗 FA 的新方法，与 FA 相比更安全、更有效 现有的方法。我们的中心假设是，使用 ROS 清除剂槲皮素进行治疗是安全的， 耐受性良好，并且会调节 FA 儿童的 ROS 水平，从而改善或逆转他们的症状 骨髓衰竭。我们自己的初步数据表明，槲皮素可以逆转 ROS 对造血的不良影响 和 FA 小鼠的胰岛素敏感性。 FA 儿童的血液和骨髓样本显示出类似的结果。 体外反应。这些数据强烈表明槲皮素将有益于刺激造血和 预防 FA 儿童的骨髓衰竭。我们的多学科团队已做好充分准备，并且可以访问 足够多的 FA 儿童群体。槲皮素是一种天然存在的抗氧化剂，存在于 正常饮食和膳食补充剂/多种维生素制剂。大多数流行病学研究表明 一般来说，槲皮素的耐受性良好，没有重大副作用。在此第一阶段研究中，我们将测试上述内容 具有以下具体目标的假设： 1. 评估长期槲皮素治疗的总体耐受性 患有 FA 的儿童。 12 名 FA 儿童将接受口服槲皮素治疗，总共 4 个月，然后 密切关注这种方法的安全性和可行性。 2. 研究槲皮素的药代动力学（Pk） 患有 FA 的儿童。为了生成槲皮素的儿科 Pk 数据，将在开始和结束时收集血液。 4个月的槲皮素治疗结束。这些数据将用于优化给药方案（如果需要）。 3. 概念验证临床研究。槲皮素对ROS减少和造血功能保存的影响 生殖干细胞储备将作为维持/预防进行性骨髓衰竭的替代标记 是的。此外，槲皮素对改善造血（血细胞计数）和胰岛素敏感性的作用将是 量化。预期结果包括证明长期槲皮素治疗是安全的、耐受性良好的。 并在 FA 患者中达到生物学相关的血液水平，这一发现将构成 随后的功效研究。预期的积极影响是，成功将带来新的一线疗法 患有 FA 的儿童，可以避免或至少推迟移植的需要。所提出的研究具有创新性， 我们认为，因为它将 ROS 作为一种新的治疗靶点，一种新颖的、可行的预防方法 通过口服槲皮素的独特干预来治疗骨髓衰竭。