Preclinical evaluation of efficacy and safety of a new iron chelator therapy in chronic spinal cord injury

新型铁螯合剂疗法治疗慢性脊髓损伤的临床前疗效和安全性评价

• 批准号: 10701817
• 负责人: PRODIP K. BOSE
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-10-01 至 2026-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10701817
• 关键词: Acceleration; Accidents; Achievement; Address; Animal Model; Animals; Attenuated; Axon; Behavioral; Bicycling; Biological Assay; Blood; Blood Vessels; Cells; Cervical spinal cord injury; Chronic; Clinical Trials; Complementary therapies; Contusions; Corticospinal Tracts; Data; Deceleration; Deposition; Deterioration; Diffuse; Diffuse Axonal Injury; Diffusion Magnetic Resonance Imaging; Disease; Dorsal; Dose; Endothelium; Evaluation; Excision; Exercise; Exercise Therapy; Florida; Functional disorder; Gait; Gliosis; Goals; Healthcare; Hemorrhage; Histologic; Human; Image; Individual; Inflammation; Inflammatory; Injury; Investigational Drugs; Investigational New Drug Application; Iron; Iron Chelation; Legal patent; Life; Magnetic Resonance Imaging; Measures; Mediating; Medical; Metabolic; Modeling; Motor; Motor Evoked Potentials; Nervous System Trauma; Neurologic; Neurology; Neuronal Plasticity; Neurons; Oral; Outcome Measure; Oxidative Stress; Pathway interactions; Pharmaceutical Preparations; Phase; Physiological; Placebo Control; Preclinical Testing; Publishing; Quality of life; Quantitative Evaluations; Reactive Oxygen Species; Regenerative capacity; Reporting; Risk Factors; Rodent; Rodent Model; Safety; Saline; Site; Source; Spinal Cord; Spinal Cord Contusions; Spinal cord injury; Sports; Symptoms; Technology; Testing; Thalassemia; Therapeutic; Time; Tissues; Toxic effect; Translations; Treatment Efficacy; United States Food and Drug Administration; Universities; Veterans; battlefield injury; behavior measurement; catalyst; cell injury; clinically relevant; cohort; design; disability; effective therapy; efficacy evaluation; functional improvement; healing; injured; innovation; nerve injury; neural; neuroinflammation; neuron loss; novel; patient oriented; phase I trial; pre-Investigational New Drug meeting; pre-clinical; preclinical evaluation; primary outcome; protective factors; rehabilitation strategy; reticulospinal tract; safety outcomes; safety testing; spasticity; therapeutically effective; therapy duration; translational potential; treatment duration; treatment effect; treatment optimization; treatment strategy; user-friendly

Cervical spinal cord injury (C-SCI) is a common and frequently devastating battlefield injury that can result in a broad range of life-long locomotor and spasticity disabilities. With advances in early evacuation and aggressive medical therapy, there are still no effective therapeutics that salvage spinal cord (SC) neurons /reduce progressive secondary damage. Acceleration/deceleration and contusion SCI cause micro-vessel shear injury, blood spinal cord barrier (BSCB) dysfunction, and hemorrhage. Iron deposited by diffuse micro-hemorrhage fuels oxidative stress and inflammation through reactive oxygen species (ROS), which further induce progressive disabilities. There is an urgent need to address both specific disabilities and risk factors for long-term progressive disabilities, and to develop effective therapies that have excellent potential for translation. The proposal will test the preclinical evaluation of the safety and efficacy of a new iron chelator, SP420, with or without a programmed locomotor therapy in a rodent model of contusion CSCI. The combination of two complementary therapies is aimed to amplify robustness necessary to significantly improve function in a chronic setting of SCI. This novel patented iron chelator will remove bleed-induced free toxic iron, a powerful catalyst of oxidative stress/inflammation, and with locomotor therapy it will upregulate neural and vascular trophic agents to protect and heal injured neural and vascular tissues. The long-term goal of these studies is to develop an effective SCI therapeutic, and to obtain sufficient preclinical evidence to support a Food and Drug Administration (FDA) Investigational New Drug (IND) application for human SCI clinical trials. Accordingly, Three Specific Aims will be tested in a clinically relevant rodent model of C-SCI. Currently, the drug has an IND for iron storage disease (e.g. Thalassemia). We have reported enduring motor (spasticity and gait) disabilities in this model. Specific Aim 1 (SA-1): Safety, efficacy and optimization of treatment duration. SP420 will be administered SQ at one fixed dose (80 mg/kg; represents the human phase II dose) in three different durations and tested against saline placebo controls. Treatment will be initiated at two post-injury chronic time points (post-injury week-4 and week-12), each using a separate cohort of animals. Quantitative physiological measures of spasticity, gait, and the integrity of axonal conduction of descending locomotor pathways functions are the primary outcomes along with clinically relevant T1/T2W, SWI/QSM, and DTI MRIs. A comprehensive list of safety outcomes will be assessed as well during the treatment. Specific Aim 2: To determine the efficacy of combined SP420 and locomotor exercise therapy in mitigating spasticity and gait disabilities. All outcome measures as stated in SA-1 will be applied. The functional/imaging/safety outcomes will be compared among the three treatment durations and two post-injury periods. Specific Aim 3 (SA-3): To determine SCI and treatment impacts on the temporal profile of iron toxicity/inflammation, cellular damage, BSCB integrity, and neuroplasticity (trophic factors). A cause-effect relationship between iron deposition, tissue damage and treatment effects of iron chelator will be studied using a combination of histological, track tracing, and immunohistochemical assays to evaluate bleed iron, oxidative stress, inflammation, markers for BSCB integrity, and neural, and vascular protective factors. We hypothesize that free bleed iron fuels oxidative stress and neuroinflammation through ROS which drives the progression of neurological damage and motor disabilities, in part. We predict that the proposed SP-420 therapy will reverse the iron-mediated neurological damage and delayed neurological sequelae. The combination of two complementary therapies will amplify robustness necessary to significantly improve function in a chronic setting of SCI. Achievement of these goals will provide innovative, non-invasive, and patient-centered technologies and treatments that will greatly facilitate treatment of veterans and civilian SCI.

颈脊髓损伤 (C-SCI) 是一种常见且经常具有破坏性的战场损伤，可导致 广泛的终生运动和痉挛残疾。随着早期疏散和 尽管积极的药物治疗，仍然没有有效的疗法可以挽救脊髓（SC）神经元 /减少渐进性二次伤害。加速/减速和挫伤SCI导致微血管 剪切损伤、血脊髓屏障（BSCB）功能障碍和出血。铁扩散沉积 微出血通过活性氧（ROS）加剧氧化应激和炎症， 进一步诱发进行性残疾。迫切需要解决特定的残疾和风险 长期进行性残疾的因素，并开发具有巨大潜力的有效疗法 用于翻译。该提案将测试新铁的安全性和有效性的临床前评估 螯合剂 SP420，在挫伤 CSCI 啮齿动物模型中进行或不进行程序化运动治疗。 两种补充疗法的结合旨在增强显着所需的稳健性 改善慢性 SCI 情况下的功能。这种新型专利铁螯合剂将消除出血引起的 游离有毒铁，氧化应激/炎症的强大催化剂，通过运动疗法，它会 上调神经和血管营养剂以保护和治愈受伤的神经和血管组织。这 这些研究的长期目标是开发有效的 SCI 治疗方法，并获得足够的临床前证据 支持食品和药物管理局 (FDA) 新药研究 (IND) 申请的证据 人体 SCI 临床试验。因此，三个具体目标将在临床相关的啮齿动物中进行测试 C-SCI 模型。目前，该药物已获得针对铁储存疾病（例如地中海贫血）的 IND。我们有 据报道，该模型存在持久的运动（痉挛和步态）障碍。具体目标 1 (SA-1)：安全、 疗效和治疗持续时间的优化。 SP420将以一种固定剂量（80 毫克/公斤；代表人类 II 期剂量）在三个不同的持续时间内并针对盐水进行测试 安慰剂对照。治疗将在受伤后的两个慢性时间点（受伤后第 4 周和 第 12 周），每个实验都使用一组单独的动物。痉挛、步态的定量生理测量 下行运动通路功能的轴突传导的完整性是主要的 结果以及临床相关的 T1/T2W、SWI/QSM 和 DTI MRI。全面的安全清单 治疗期间也会评估结果。具体目标 2：确定功效 SP420 和运动运动疗法相结合，可减轻痉挛和步态障碍。所有结果 将采用 SA-1 中规定的措施。将比较功能/成像/安全结果 在三个治疗持续时间和两个受伤后时期之间。具体目标 3 (SA-3)：确定 SCI 和治疗对铁毒性/炎症、细胞损伤、BSCB 时间分布的影响 完整性和神经可塑性（营养因子）。铁沉积与组织之间的因果关系 将结合组织学、追踪技术来研究铁螯合剂的损伤和治疗效果 追踪和免疫组织化学测定，以评估出血铁、氧化应激、炎症、标记物 BSCB 完整性以及神经和血管保护因素。我们假设自由放气铁燃料 通过 ROS 产生氧化应激和神经炎症，从而驱动神经损伤的进展 和部分运动障碍。我们预测所提出的 SP-420 疗法将逆转铁介导的 神经损伤和迟发性神经后遗症。两种互补的组合 治疗将增强显着改善慢性 SCI 功能所需的稳健性。 这些目标的实现将提供创新、非侵入性和以患者为中心的技术和 的治疗将极大地促进退伍军人和平民脊髓损伤的治疗。