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）： 目前针对范可尼贫血 (FA) 和骨髓衰竭儿童的治疗方法、雄激素或骨髓移植与显着的发病率和死亡率相关。因此，需要一种副作用越来越少的新方法，对动物和人类的研究表明，高水平的全身活性氧 (ROS) 和造血祖细胞对 ROS 的敏感性增加在疾病的发病机制中发挥着关键作用。这些儿童的骨髓衰竭。长期目标是阻止 FA 中骨髓衰竭的进展并降低相关的发病率和死亡率。该申请的总体目标是开发 1 期水平，这是一种比现有方法更安全、更有效的 FA 治疗新方法。中心假设是确定 ROS 清除剂槲皮素治疗是否安全、耐​​受性良好，并能调节 FA 儿童的 ROS 水平，从而改善或逆转他们的骨髓衰竭。初步数据似乎表明，槲皮素可以逆转 FA 小鼠中 ROS 对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表现出类似的反应。数据似乎表明槲皮素有助于刺激 FA 儿童的造血和预防骨髓衰竭。 槲皮素是一种天然存在的抗氧化剂，存在于正常饮食、膳食补充剂和多种维生素制剂中。大多数流行病学研究表明，一般来说，槲皮素的耐受性良好，没有重大副作用。这项 1 期研究将测试上述假设，具体目标如下： 1. 评估 FA 儿童对长期槲皮素治疗的总体耐受性。 12 名 FA 儿童将接受口服槲皮素治疗总共 4 个月，并密切随访该方法的安全性和可行性。 2. 研究药代动力学（pK） FA 儿童中的槲皮素。为了生成槲皮素的儿科 pK 数据，将收集血液 在 4 个月的槲皮素治疗开始时和结束时。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。槲皮素的影响 ROS 的减少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，槲皮素对改善造血（血细胞计数）和胰岛素敏感性的作用也将被量化。预期结果包括证明长期槲皮素治疗是安全的，耐受性良好，并且可以在 FA 患者中达到生物学相关的血液水平，这一发现将 为后续功效研究奠定基础。