Abstract. The purpose of this SBIR Phase I application is to develop new iron chelating drugs for the prevention and treatment of iron overload-induced bone loss in patients with sickle cell disease (SCD, a rare blood disorder in the USA). In SCD patients, osteopenia and osteoporosis are major complications with a very high prevalence (around 80%). Despite the significant clinical impact, there is no specific and effective therapeutic for such conditions. Iron overload and its associated free radical oxidative damage in skeletal tissues have been recognized as major causes of the condition in SCD patients. However, none of the current iron chelating drugs (deferoxamine, deferiprone and deferasirox) have yet shown the ability to protect the skeleton from iron deposition and oxidative damage, in order to effectively prevent and treat SCD-induced bone loss. Therefore, there is an unmet need for the development of new chelating drugs that can target the pathogenesis of SCD bone loss. Here, our goal is to close this gap by further developing our chelators as effective therapeutics for bone loss in SCD patients. This technology has been protected by two US patents and licensed to NanoMedic (a University of Utah startup company) for further development towards commercialization. Our hypotheses are (1) that our chelators have the ability to effectively reach the bone and remove excess iron, thus mitigating skeletal iron-associated free radical damage and bone loss in SCD patient; and (2) that the chelators combined with vitamin E, an antioxidant as an adjuvant, are more effective in preventing SCD-bone loss. These novel hypotheses are strongly supported by our studies. To demonstrate our hypotheses and accomplish our goal, we propose the following Aim to prepare/scale up our chelators and to evaluate the bone protective efficacies of the chelator alone and the chelator/vitamin E combination in an established iron overload mouse model of SCD. The levels of skeletal iron and oxidative damage will be simultaneously examined with our unique electron paramagnetic resonance (EPR) technology. The bone protective capabilities of the chelator and its combination with vitamin E will be evaluated using bone dynamic histomorphometric and computed tomography analyses as well as other techniques. Systemic iron levels and potential toxicity associated with the treatment will also be examined with standard methods. We believe that this Phase I study will demonstrate our hypotheses and the deservedness for further development to fulfill an investigational new drug submission to the FDA in a following Phase II study. To the best of our knowledge, our laboratory is the only one to develop new specific, effective chelating drugs for iron-associated bone loss, and we are confident that such drug development will be successfully accomplished because of our multi- disciplinary expertise in chelating drug development, bone biology, bone drug evaluation and bone EPR technology. ...