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: 8896309
• 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 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8896309
• 关键词: Phase; Study; Quercetin; Treatment; Fanconi

DESCRIPTION (provided by applicant): Current therapies for children with Fanconi anemia (FA) and bone marrow failure, androgens or bone marrow transplantation, are associated with significant morbidity and mortality. Thus, a need for a novel approach with 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. The 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 is to develop a Phase 1 level, a novel approach to treatment of FA that is safer and more efficacious compared to existing approaches. The central hypothesis is to determine if 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. Preliminary data appears to 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 responses in vitro. The data appear to suggest that quercetin will be beneficial in stimulating hematopoiesis and preventing marrow failure in children with FA. Quercetin is a naturally occurring anti-oxidant, found in the normal diet and in dietary supplements and multivitamin preparations. Most epidemiological studies have shown that in general, quercetin is well tolerated without major side effects. This Phase 1 study 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 followed closely for the 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 hematopoietic stem cell reserve will serve as surrogate markers for maintenance and prevention of progressive marrow failure. 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 tolerated and achieves biologically relevant blood levels in patients with FA, a finding which will form the basis of subsequent efficacy studies.

描述（由申请人提供）： 目前针对Fanconi贫血（FA）和骨髓衰竭（雄激素或骨髓移植）儿童的疗法与显着的发病率和死亡率有关。因此，需要一种在动物和人类中具有较少副作用研究的新型方法表明，造血祖细胞的高水平的全身性活性氧（ROS）和造血祖细胞对ROS的敏感性提高在这些儿童的骨髓衰竭发病机理中起关键作用。长期的目标是阻止FA中骨髓衰竭的进展，并降低相关的发病率和死亡率。该应用程序的总体目的是开发1阶段水平，这是一种与现有方法相比，一种新型的FA治疗方法，更安全，更有效。中心假设是确定用ROS可寻求槲皮素治疗是否安全，耐受性良好，并且会调节FA儿童的ROS水平，而FA儿童的ROS水平又会改善或逆转其骨髓衰竭。初步数据似乎表明槲皮素会逆转ROS对FA小鼠造血和胰岛素敏感性的不良影响。来自FA儿童的血液和骨髓样品在体外显示出相似的反应。数据似乎表明槲皮素将有益于刺激造血和防止FA儿童的骨髓衰竭。 槲皮素是一种天然存在的抗氧化剂，在正常饮食以及饮食补充剂和多种维生素制剂中发现。大多数流行病学研究表明，槲皮素的耐受性良好而没有重大副作用。这项1阶段研究将以以下特定目的检验上述假设：1。评估FA儿童长期槲皮素治疗的总体耐受性。十二名FA儿童将用口服槲皮素治疗4个月，并紧随其后，以确保这种方法的安全性和可行性。 2。研究药代动力学（PK） 槲皮素在Fa的儿童中。为了生成槲皮素的小儿PK数据，将收集血液 在槲皮素治疗的开始和4个月结束时。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 造血干细胞储备的ROS减少和保存将作为维持和预防进行性骨髓衰竭的替代标记。 另外，将量化槲皮素对改善造血（血液计数）和胰岛素敏感性的影响。预期的结果包括证明，长期槲皮素治疗是安全的，耐受性的，并且在FA患者中实现了与生物学相关的血液水平，这一发现将会 构成了随后的功效研究的基础。