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.
By any measure, Fanconi anemia (FA) is an orphan disease, with an overall prevalence of 1 to 5 per million and an estimated carrier frequency of 1 in 200 to 1 in 300 in most populations, with limited therapeutic options. This Phase 1 study will be the first step in developing quercetin, a naturally occurring anti-oxidant, as a simpler, safer and novel therapeutic approach for prevention of marrow failure in FA, ultimately gaining FDA approval for the same. This project is relevant to the FDAs mission, to advance the evaluation and development of products (drugs, biologics, devices, or medical foods) that demonstrate promise for the diagnosis and/or treatment of rare dis- eases or conditions. This study is also consistent with a new congressionally mandated program that calls for preclinical and early clinical development of new drugs for rare and neglected diseases, and development of new technologies and paradigms to improve the efficiency of therapeutic development for these diseases, as well as the Integrated National Strategy to Accelerate Research and Product Development for Rare Diseases recently created by NIH and the Institute of Medicine (IOM).