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.

项目摘要/摘要 目前针对Fanconi贫血（FA）和骨髓衰竭的儿童的疗法，即雄激素或 骨髓移植与明显的发病率和死亡率有关。因此，显然有一个 需要一种新的方法，其副作用较少且较少。对动物和人类的研究 表明高水平的全身活性氧（ROS）和造血性敏感性提高 ROS的祖细胞在这些儿童的骨髓衰竭发病机理中起关键作用。我们的长期目标 是为了阻止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的长期目标的下一步 在第一阶段级别上，速丝是一种新型的FA治疗方法，与 现有方法。我们的核心假设是，用ROS ROS清除槲皮素治疗将是安全的， 耐受性良好，并将调节FA儿童的ROS水平，进而将其改善或逆转他们 骨髓衰竭。我们自己的初步数据表明，槲皮素会逆转ROS对造血的不良影响 和FA小鼠的胰岛素敏感性。来自FA儿童的血液和骨髓样品显示出相似的重新 体外发起人。这些数据强烈表明槲皮素将有益于刺激造血和 防止FA儿童的骨髓衰竭。我们的多学科团队已经做好了充分的准备，并且可以访问 足够大的FA儿童。槲皮素是一种天然存在的抗氧化剂，发现 正常饮食和饮食补充剂/多种维生素制剂。大多数流行病学研究表明 通常，槲皮素的耐受性很好，没有重大副作用。在此阶段1研究中，我们将测试上述 假设具有以下特定目的：1。评估长期槲皮素治疗的总体耐受性 患有足总的孩子。十二名FA儿童将接受口服槲皮素治疗，总共4个月，然后 为了安全性和可行性而紧密降低。 2。槲皮素的研究药代动力学（PK） 患有足总的孩子。为了生成槲皮素的儿科PK数据，将在开始时和 槲皮素治疗4个月结束。这些数据将用于优化剂量时间表（如果需要）。 3。 概念证明临床研究。槲皮素对造血的减少和保存的影响 Etic干细胞储备将作为维持/预防进行性骨髓失败的替代标记 ure。此外，槲皮素对改善造血（血液计数）和胰岛素敏感性的影响将是 量化。预期的结果包括证明长期槲皮素治疗是安全的，可耐受的 ED并达到FA患者的生物学相关血液水平，这一发现将构成 随后的功效研究。预期的积极影响是，成功将导致新的第一线治疗 FA的儿童，消除或至少延迟了移植的需求。拟议的研究具有创新性，在 我们的观点，因为它将ROS作为一种新颖的治疗靶标的小说结合在一起，以一种可行的方法来进行预见。 口服槲皮素的独特干预术的骨髓衰竭。