Phase 1 Study of Quercetin for the Treatment of Fanconi Anemia

描述(由申请人提供)： 目前治疗儿童Fanconi贫血(FA)和骨髓衰竭、雄激素或骨髓移植的方法与显著的发病率和死亡率有关。因此，需要一种副作用少且不严重的新方法，在动物和人类中的研究表明，高水平的系统活性氧物种(ROS)和造血祖细胞对ROS的敏感性增加在这些儿童骨髓衰竭的发病机制中发挥了关键作用。长期目标是阻止FA患者骨髓衰竭的进展，降低相关的发病率和死亡率。这项应用的总体目标是开发一种阶段1水平，一种与现有方法相比更安全和更有效的治疗FA的新方法。中心假设是确定使用ROS清除剂Qercetin治疗是否安全、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他们的骨髓衰竭。初步数据似乎表明，栎素可以逆转ROS对FA小鼠的造血和胰岛素敏感性的不良影响。FA儿童的血液和骨髓样本在体外也表现出类似的反应。这些数据似乎表明，在FA的儿童中，Quercetin将有益于刺激造血和预防骨髓衰竭。槲皮素是一种天然抗氧化剂，存在于正常饮食、膳食补充剂和复合维生素制剂中。大多数流行病学研究表明，总的来说，槲皮素耐受性良好，没有重大副作用。这项第一阶段的研究将验证上述假设，具体目的如下：1.评估长期服用槲皮素治疗FA儿童的总体耐受性。12名FA儿童将接受为期4个月的口服槲皮素治疗，并密切跟踪观察该方法的安全性和可行性。2.药代动力学(PK)研究 槲皮素在儿童FA中的应用为了生成儿科PK数据，将采集血液 在4个月的治疗开始和结束时。这些数据将用于优化配药计划(如果需要)。3.概念验证性临床研究。槲皮素对大鼠血管紧张素的影响 ROS的降低和造血干细胞储备的保存将作为维持和预防进行性骨髓衰竭的替代标志物。此外，还将量化槲皮素在改善造血(血细胞计数)和胰岛素敏感性方面的作用。预期的结果包括证明长期的栎素疗法是安全的，耐受性良好，并在FA患者中达到生物相关的血液水平，这一发现将 形成了后续疗效研究的基础。

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.