Phase 1 Study of Quercetin for the Treatment of Fanconi Anemia

项目摘要/摘要 目前治疗儿童范可尼贫血(FA)和骨髓衰竭的方法，即雄激素或 骨髓移植，与严重的发病率和死亡率有关。因此，显然存在一个 需要一种副作用更少、更不严重的新方法。对动物和人类的研究 提示全身活性氧簇(ROS)水平升高和造血敏感性增加 ROS的祖细胞在这些儿童骨髓衰竭的发病机制中起着关键作用。我们的长期目标 目的是阻断FA患者骨髓衰竭的进展，降低相关的发病率和死亡率。这个 这项申请的整体目标，是迈向我们长远目标的下一步，是要减少- FELL，在第一阶段，一种治疗FA的新方法，与 现有的方法。我们的中心假设是，使用ROS清除剂槲皮素治疗是安全的， 耐受性良好，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。我们自己的初步数据显示，槲皮素可以逆转ROS对造血的不良影响 以及FA小鼠的胰岛素敏感性。来自FA儿童的血液和骨髓样本显示类似的结果。 体外试验中的回声。这些数据有力地表明，栎素将有益于刺激造血和 预防儿童FA的骨髓衰竭。我们的多学科团队做好了充分的准备，将有机会 足够量的FA儿童人口。槲皮素是一种天然抗氧化剂，存在于 正常饮食和膳食补充剂/复合维生素制剂。大多数流行病学研究表明， 总体而言，栎素耐受性良好，没有重大副作用。在此阶段1研究中，我们将测试以上内容 有以下具体目的的假说：1.评估长期服用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，疗程共4个月，随后- 为这种方法的安全性和可行性而密切关注。2.研究了槲皮素在大鼠体内的药代动力学 患有FA的儿童。为了生成儿科PK数据，将在开始和结束时采集血液 治疗4个月后结束。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。Quercetin对ROS降低和造血保护的影响 Etic干细胞储备将作为维持/预防进行性骨髓衰竭的替代标志。 尤尔。此外，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将是 量化的。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。 ED和达到FA患者的生物相关血液水平，这一发现将构成 随后的疗效研究。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，避免或至少推迟了移植的需要。拟议的研究是创新的，在 我们认为，由于它将ROS作为一种新的治疗靶点，这是一种可行的方法，适用于预防- 用独特的口服槲皮素干预治疗骨髓衰竭。

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.