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.

项目总结/摘要 目前治疗范可尼贫血（FA）和骨髓衰竭的儿童，即雄激素或 骨髓移植与显著的发病率和死亡率相关。因此，显然有一个 需要一种新的方法，具有更少和更不严重的副作用。动物和人类研究 表明高水平全身活性氧（ROS）和造血敏感性增加 ROS祖细胞在这些儿童骨髓衰竭的发病机制中起关键作用。我们的长期目标 目的是阻断FA中骨髓衰竭的进展，降低相关的发病率和死亡率。的 本申请的总体目标是实现我们的长期目标的下一步，目的是： velop，1期水平，一种治疗FA的新方法，与 现有的方法。我们的中心假设是，用ROS清除剂槲皮素治疗是安全的， 耐受性良好，并将调节FA儿童的ROS水平，这反过来将改善或逆转其 骨髓衰竭我们自己的初步数据表明，槲皮素逆转ROS对造血的不良影响 和胰岛素敏感性。FA儿童的血液和骨髓样本显示出类似的结果， sponses in vitro.这些数据强烈表明，槲皮素将有利于刺激造血， 预防FA患儿的骨髓衰竭。我们的多学科团队已经做好充分准备， 足够多的FA儿童。槲皮素是一种天然存在的抗氧化剂， 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，槲皮素耐受性良好，没有严重的副作用。在这项1期研究中，我们将测试上述内容 假设有以下具体目标：1。评估长期槲皮素治疗的总体耐受性， 孩子们FA 12名FA儿童将接受口服槲皮素治疗，共4个月，随后 密切关注这种方法的安全性和可行性。2.槲皮素在大鼠体内的药代动力学研究 孩子们FA为了生成槲皮素的儿科PK数据，将在开始和结束时采集血液。 槲皮素治疗4个月结束。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。槲皮素对活性氧的降低及造血功能的保护作用 胚胎干细胞储备将作为维持/预防进行性骨髓衰竭的替代标志物- 当然。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，耐受性好， 艾德并在FA患者中达到生物学相关的血液水平，这一发现将成为 随后的功效研究。预期的积极影响是，成功将导致新的一线治疗， 患有FA的儿童，避免或至少延迟移植的需要。该研究具有创新性， 我们的观点，因为它将ROS作为一种新的治疗靶点，一种新的，可行的预防方法， 通过口服槲皮素的独特干预治疗骨髓衰竭。