Developing novel therapeutic approaches for osteopenia and osteoporosis in patients with sickle cell disease

抽象的。这项SBIR第一阶段应用的目的是开发新的铁络合药物，用于 一种罕见的镰状细胞病患者铁超负荷所致骨丢失的防治 美国的血液疾病)。在SCD患者中，骨量减少和骨质疏松症是主要的并发症， 高患病率(约80%)。尽管有重大的临床影响，但没有具体和有效的 治疗此类疾病的药物。骨骼中铁超载及其相关的自由基氧化损伤 组织已被认为是SCD患者病情的主要原因。然而，目前没有一个 铁螯合药物(去铁胺、去铁酮和去铁胺)尚未显示出保护 防止骨骼铁沉积和氧化损伤，以更有效地预防和治疗SCD诱导的骨 损失。因此，有一个尚未得到满足的需求，开发新的螯合药物，可以靶向 SCD骨丢失的发病机制。在这里，我们的目标是通过进一步开发我们的螯合剂来缩小这一差距 SCD患者骨丢失的有效治疗方法。这项技术受到两项美国专利的保护 并授权给NanoMedic(犹他大学的一家初创公司)，用于进一步开发 商业化。我们的假设是：(1)我们的螯合剂有能力有效地接触到骨骼和 清除多余的铁，从而减轻SCD患者骨骼铁相关的自由基损伤和骨丢失； 以及(2)配合维生素E(一种抗氧化剂)作为佐剂的螯合剂更有效 防止SCD-骨丢失。这些新颖的假设得到了我们的研究的有力支持。来展示我们的 假设和实现我们的目标，我们提出以下目标，以制备/放大我们的螯合剂和 评价单独使用螯合剂和螯合剂/维生素E联合用药的骨保护效果 建立SCD铁超负荷小鼠模型。骨骼铁和氧化损伤的水平将是 同时使用我们独特的电子顺磁共振(EPR)技术进行检测。这块骨头 将使用骨动力学来评估螯合剂及其与维生素E的组合的保护能力 组织形态计量学和计算机断层扫描分析以及其他技术。全身铁水平和 与治疗相关的潜在毒性也将用标准方法进行检查。我们相信 这项第一阶段的研究将证明我们的假设和进一步发展的必要性，以实现 在第二阶段研究之后的一项研究中，向FDA提交了研究性新药。据我们所知， 我们的实验室是唯一一家开发出治疗铁相关骨丢失的新型特效螯合药物的实验室， 我们有信心，这种药物的开发将成功完成，因为我们的多 在螯合药物开发、骨生物学、骨药物评价和骨EPR方面的专业知识 技术我们也有信心，我们的发展将把新的、有效的疗法带到全球 因此，严重影响了SCD患者骨质疏松和骨量减少的临床治疗。

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. We also have confidence that our development will bring new, effective therapeutics into the global market, thus significantly impacting the clinical management of osteoporosis and osteopenia in SCD patients.