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

颈髓损伤(C-SCI)是一种常见且经常具有破坏性的战场损伤，可导致 在广泛的终生运动和痉挛障碍中。随着早期疏散和 积极的药物治疗，仍然没有有效的治疗方法来挽救脊髓(SC)神经元 /减少渐进性的二次伤害。加减速和挫伤致脊髓微血管损伤 剪切伤、血脊髓屏障(BSCB)功能障碍和出血。漫反射沉积的铁 微出血通过活性氧物种(ROS)加剧氧化应激和炎症，其中 进一步导致进展性残疾。迫切需要解决具体的残疾和风险问题。 长期进展性残疾的因素，并开发具有极大潜力的有效疗法 以供翻译。该提案将测试一种新铁的安全性和有效性的临床前评估 螯合剂SP420，在CSCI啮齿动物模型中应用或不应用程序化运动疗法。 两种互补疗法的结合旨在增强必要的健壮性 改善慢性脊髓损伤患者的功能。这种新的专利铁络合剂将消除出血引起的 游离的有毒铁是氧化应激/炎症的强大催化剂，通过运动疗法，它将 上调神经和血管营养剂，以保护和修复受损的神经和血管组织。这个 这些研究的长期目标是开发有效的脊髓损伤治疗方法，并获得足够的临床前治疗。 支持食品和药物管理局(FDA)研究新药(IND)申请的证据 人类脊髓损伤临床试验。因此，将在临床相关的啮齿动物身上测试三个特定的目标 C-SCI模型。目前，该药物具有治疗铁储存疾病(如地中海贫血)的IND。我们有 在这个模型中，报告了持久的运动(痉挛和步态)障碍。具体目标1(SA-1)：安全、 疗效与疗程优化。SP420将以一个固定剂量(80%)给予SQ Mg/kg；代表人体第二阶段剂量)在三个不同的持续时间内，并在生理盐水中进行测试 安慰剂对照组。治疗将在两个受伤后慢性时间点开始(受伤后4周和 12周)，每组使用一组单独的动物。痉挛、步态、 而轴突传导的完整性是下行运动通路功能的首要 结果以及临床相关的T1/T2W、SWI/QSM和DTI磁共振成像。全面的安全清单 在治疗期间也将评估结果。具体目标2：确定 SP420联合运动训练疗法缓解痉挛和步态障碍。所有结果 将实施SA-1中规定的措施。功能/成像/安全结果将进行比较 在三个疗程和两个伤后时期。具体目标3(SA-3)：确定 脊髓损伤和治疗对铁中毒/炎症、细胞损伤、BSCB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 铁络合剂的损伤和治疗效果将采用组织学、径迹相结合的方法进行研究 示踪和免疫组织化学分析以评估出血铁、氧化应激、炎症、标志物 对于BSCB的完整性，以及神经和血管保护因素。我们假设自由放血的铁燃料 氧化应激和神经炎症通过ROS驱动神经损伤的进展 和运动障碍，部分是。我们预测，拟议的SP-420疗法将逆转铁介导的 神经损伤和延迟性神经后遗症。两个互补的组合 治疗将增强在慢性脊髓损伤环境中显著改善功能所必需的健壮性。 实现这些目标将提供创新、非侵入性和以患者为中心的技术和 治疗将极大地促进退伍军人和平民脊髓损伤的治疗。

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.