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.

摘要：本次 SBIR 一期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，一种罕见的疾病）患者铁过载引起的骨质流失 在美国的血液疾病中），骨质减少和骨质疏松是 SCD 患者的主要并发症。 尽管有显着的临床影响，但尚无具体有效的方法。 治疗此类疾病及其相关的骨骼自由基氧化损伤。 组织已被认为是 SCD 患者病情的主要原因，但目前还没有。 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 因此，开发能够靶向该损失的新螯合药物的需求尚未得到满足。 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。 针对 SCD 患者骨质流失的有效疗法该技术已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）进一步开发 我们的假设是（1）我们的螯合剂能够有效到达骨骼并 去除多余的铁，从而减轻 SCD 患者骨骼铁相关的自由基损伤和骨质流失； (2) 螯合剂与抗氧化剂维生素 E 结合作为佐剂，在以下方面更有效： 我们的研究有力地支持了这些新的假设。 假设并实现我们的目标，我们提出以下目标来准备/扩大我们的螯合剂并 评估单独螯合剂和螯合剂/维生素 E 组合的骨保护功效 建立了铁超负荷的SCD小鼠模型，骨骼铁水平和氧化损伤将呈正相关。 同时使用我们独特的电子顺磁共振 (EPR) 技术进行检查。 将使用骨动力学评估螯合剂及其与维生素 E 组合的保护能力 组织形态学和计算机断层扫描分析以及其他技术。 我们相信，与治疗相关的潜在毒性也将通过标准方法进行检查。 这项第一阶段的研究将证明我们的假设以及进一步发展的必要性，以实现 据我们所知，在接下来的 II 期研究中向 FDA 提交了研究性新药。 我们的实验室是唯一一家开发新的特异性、有效的螯合药物来治疗与铁相关的骨质流失的实验室， 我们相信，由于我们的多方合作，此类药物的开发将会成功完成。 螯合药物开发、骨生物学、骨药物评价和骨EPR方面的学科专业知识 我们也相信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 患者骨质疏松和骨质减少的临床管理。