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

开发镰状细胞病患者骨质减少和骨质疏松症的新治疗方法

• 批准号: 9976289
• 负责人: GANG LIU
• 金额: $ 24.85万
• 依托单位: NANOMEDIC, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-10 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9976289
• 关键词: Adjuvant; Affect; African American; Antioxidants; Biological Markers; Biology; Blood; Bone Diseases; Brain; Chelating Agents; Chelation Therapy; Clinical; Clinical Management; Deferoxamine; Deposition; Development; Disease; Dose; Drug Evaluation; Electron Spin Resonance Spectroscopy; Enzyme-Linked Immunosorbent Assay; Erythroid; Estrogens; Evaluation; Excision; Excretory function; Formulation; Free Radicals; Goals; Heart; Hematological Disease; High Prevalence; Inherited; Investigational Drugs; Iron; Iron Chelating Agents; Iron Overload; Kidney; Laboratories; Legal patent; Liver; Longevity; Measures; Medicine; Metabolism; Methods; Oral; Organ; Osteopenia; Osteoporosis; Pathogenesis; Pathology; Patients; Pharmaceutical Preparations; Pharmacology and Toxicology; Phase; Play; Prevalence; Prevention; Quality of life; Rattus; Reporting; Role; Serum; Sickle Cell Anemia; Skeleton; Small Business Innovation Research Grant; Spleen; Techniques; Technology; Testing; Therapeutic; Toxic effect; Toxicology; Transfusion; Treatment Efficacy; Treatment Protocols; United States; United States National Institutes of Health; Universities; Utah; Vitamin E; X-Ray Computed Tomography; absorption; bone; bone loss; bone turnover; chelation; commercialization; drug development; effective therapy; improved; innovation; iron oxidation; mouse model; multidisciplinary; new technology; novel; novel therapeutic intervention; novel therapeutics; oxidation; oxidative damage; phase 1 study; phase 2 study; prevent; protective efficacy; scale up; skeletal; skeletal tissue; soft tissue; tool

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.

抽象的。 SBIR I期应用的目的是开发新的铁螯合药物 镰状细胞疾病患者的铁超载引起的骨质流失（SCD）（罕见的） 美国的血液疾病）。在SCD患者中，骨质减少症和骨质疏松症是主要并发症 高患病率（约80％）。尽管临床影响重大，但没有具体和有效 治疗这种情况。铁超载及其相关的骨骼中的自由基氧化物损害 在SCD患者中，组织被认为是病情的主要原因。但是，没有一个 铁螯合药物（脱氟胺，脱氟酮和脱发）尚未表明保护能力 铁沉积和氧化损伤的骨骼，以有效预防和治疗SCD诱导的骨头 损失。因此，需要开发新的螯合药物的需求 SCD骨质流失的发病机理。在这里，我们的目标是通过进一步发展我们的螯合剂作为 SCD患者骨质流失的有效治疗。这项技术已受到两项美国专利的保护 并获得纳米医学（犹他大学的初创公司）的许可，以进一步发展 商业化。我们的假设是（1）我们的螯合剂具有有效到达骨骼的能力， 去除超过铁，从而减轻SCD患者中与骨骼铁相关的自由基损伤和骨质流失； （2）螯合剂与维生素E（一种可调节的抗氧化剂）相结合，在 防止SCD骨损失。这些新的假设得到了我们的研究强烈支持。展示我们的 假设并实现我们的目标，我们提出以下目标，以准备/扩展我们的螯合剂并 评估单独的螯合剂和螯合剂/维生素E组合的骨骼保护有效性 已建立的SCD的铁超载鼠标模型。骨骼铁和氧化损伤的水平将是 同样，我们使用我们独特的电子顺磁共振（EPR）技术进行了研究。骨头 螯合剂的保护能力及其与维生素E的组合将使用骨动力学评估 组织形态计量学和计算机断层扫描分析以及其他技术。系统性铁水平和 与治疗相关的潜在毒性也将使用标准方法检查。我们相信 这一I阶段研究将证明我们的假设和应有的进一步发展的应有性 在接下来的II阶段研究中，调查新药提交给FDA。据我们所知， 我们的实验室是唯一开发新的特异性，有效螯合药物以进行铁相关骨质流失的人， 而且我们有信心，由于我们的多种多样，这种药物开发将成功完成 螯合药物开发，骨骼生物学，骨骼药物评估和骨EPR方面的纪律专业知识 技术。我们还相信我们的发展将为全球带来新的有效疗法 市场，从而显着影响SCD患者的骨质疏松症和骨质减少症的临床管理。