Phase 1 Study of Quercetin for the Treatment of Fanconi Anemia

<p>DESCRIPTION: 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) ofquercetin in children with FA. To generate pediatric pK data for quercetin, blood will be collectedat 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 onROS 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.</p>