In the past funding period of the OHSU Fanconi Anemia Program Project we succeeded in discovering new drug targets and small molecules for FA therapy. All of these candidates have clinical potential and we are on the threshold of new interventions for this severe disease. The key goal of the project in the next funding period is to prioritize a single drug regimen from our small list of candidates and to generate the preclinical data needed for starting a clinical trial soon.This Program Project will use a multidisciplinary approach to achieve this goal. The clinical disciplines represented include pediatrics, hematology, oncology and medical genetics. The scientific areas of expertise include molecular hematology, xenotransplantation, DNA repair, cell biology and mouse genetics. Project 1 (Grompe Lab at OHSU) will explore drugs that have already shown promise in FA mouse models such as metformin, p38 MAPK inhibitors, antioxidants and androgens, both singly and in combination. Project 2 (D’Andrea Lab at Harvard) will focus on inhibitors of the TGF- pathway for the treatment of FA. This is a new class of medications being tested by multiple pharmaceutical companies to treat inflammatory diseases. We have found that these medicines can significantly improve blood formation in FA. Project 3 (Shimamura Lab at Harvard) will use primary human cells from FA patients (bone marrow specimens) to study the compounds from projects 1 and 2. In addition, the regulatory groundwork for a clinical trial will be done. These scientific projects will be supported by technical cores which can provide expertise in DNA repair, human patient specimen procurement and testing human bone marrow cells in living mice. Drugs may be developed from this work that help improve blood counts in individuals with different bone marrow failure disorders, including leukemia and aplastic anemia.