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

抽象的。SBIR第一阶段申请的目的是开发新的铁螯合药物， 预防和治疗镰状细胞病（SCD，一种罕见的 美国的血液病）。在SCD患者中，骨量减少和骨质疏松症是主要并发症， 高流行率（约80%）。尽管有显著的临床影响，但没有特异性和有效的 治疗此类疾病。骨骼肌铁超载及其相关的自由基氧化损伤 组织已经被认为是SCD患者中病症的主要原因。然而，目前没有一个 铁螯合药物（去铁胺、去铁酮和地拉罗司）尚未显示出保护铁的能力。 骨骼免受铁沉积和氧化损伤，从而有效预防和治疗SCD引起的骨 损失因此，对于开发能够靶向所述靶向的新螯合药物存在未满足的需求。 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， 有效治疗SCD患者的骨丢失。这项技术已经受到两项美国专利的保护 并授权给NanoMedic（一家犹他州大学的创业公司），以进一步发展， 商业化我们的假设是（1）我们的螯合剂有能力有效地到达骨骼， 去除多余的铁，从而减轻SCD患者中与骨骼铁相关的自由基损伤和骨丢失; 和（2）螯合剂与作为辅助剂的抗氧化剂维生素E组合， 防止SCD骨丢失。我们的研究有力地支持了这些新的假设。展示我们 假设并实现我们的目标，我们提出以下目的来制备/扩大我们的螯合剂并 评价单独的螯合剂和螯合剂/维生素E组合的骨保护功效， 建立SCD小鼠铁负荷模型。骨骼铁和氧化损伤的水平将 同时用我们独特的电子顺磁共振（EPR）技术进行检测。骨 将使用骨动力学评估螯合剂及其与维生素E的组合的保护能力。 组织形态测量和计算机断层扫描分析以及其他技术。全身铁水平和 还将用标准方法检查与治疗相关的潜在毒性。我们认为 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，以实现一个 在随后的II期研究中向FDA提交研究性新药。据我们所知， 我们的实验室是唯一一个开发新的特异性，有效的螯合药物的铁相关的骨丢失， 我们相信，由于我们的多方面努力， 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，我们的发展将为全球带来新的，有效的治疗方法。 市场，从而显着影响SCD患者骨质疏松症和骨量减少的临床管理。

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.