Neuronal Protective Nanoparticles for Treating Acute SCI

用于治疗急性 SCI 的神经元保护纳米颗粒

• 批准号: 9252601
• 负责人: VINOD D LABHASETWAR
• 金额: $ 44.61万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9252601
• 关键词: Acute; Address; Affect; Aftercare; Anatomy; Animal Model; Animals; Antioxidants; Bladder; Blood; Caring; Cells; Chest; Clinical; Control Animal; Demyelinations; Deposition; Dose; Drug usage; Electromyography; Encapsulated; Ensure; Environment; Enzymes; Event; Extravasation; FDA approved; Family Caregiver; Functional disorder; Generations; Genes; Goals; Histologic; Inflammatory; Injury; Lesion; Leukocytes; Locomotor Recovery; Mediating; Methylprednisolone; Microglia; Modeling; Molecular; Molecular Weight; Morbidity - disease rate; Muscular Atrophy; Natural regeneration; Nature; Neurons; Oligodendroglia; Oxidative Stress; Paralysed; Paraplegia; Patients; Perception; Physiological; Plasticizers; Play; Polymers; Population; Rattus; Reactive Oxygen Species; Recovery; Recovery of Function; Role; Secondary to; Sensory; Site; Spinal; Spinal Cord; Spinal cord injury; Spinal cord injury patients; Stem cells; Superoxide Dismutase; Syringomyelia; Testing; Therapeutic; Therapeutic Intervention; Thermal Hyperalgesias; Time; Tissues; Toxic effect; Traumatic CNS injury; Wound Healing; antioxidant enzyme; base; catalase; chemokine; clinically relevant; cost; cytokine; cytotoxic; design; disability; effective therapy; global health; improved; injured; intravenous administration; kinematics; macrophage; mechanical allodynia; mortality; nanoparticle; neurogenesis; neurological recovery; neuron apoptosis; neuron loss; neurophysiology; neuroprotection; neutrophil; oxidative damage; preclinical efficacy; public health relevance; repaired; response; socioeconomics; uptake

 DESCRIPTION (provided by applicant): We have designed neuronal Protective Nanoparticles (Pro-NPs) with a unique composition containing antioxidant enzymes that are released in active form over a sustained period of time. Our goal is to test their efficacy for treating acute spinal cord injury (SCI). Disability due to SCI is a major global health issue, affecting mainly the young population. Nearly 1.3 million people in the US are living with paralysis due to SCI, and it costs $40.5 billion annually for their care. At present, there is no effective treatment that can achieve functional recovery following SCI. The pathophysiology of traumatic SCI involves the initial physical impact, which leads to secondary injury cascades of degenerative cellular and molecular events. The secondary injury spreads along the spinal cord over time, which adds new levels of disability and has devastating effects. Reactive oxygen species (ROS) formation at the impact site is an important component of these secondary injury cascades. We hypothesize that efficient and sustained delivery of antioxidants to the lesion site could alleviat the oxidative stress-mediated degenerative events following SCI and promote endogenous neuronal repair mechanisms, leading to recovery of locomotors, neurological, and physiological functions. In preliminary studies in a thoracic rat model of traumatic SCI, we demonstrated that following intravenous administration at 3 hr. post-injury, Pro-NPs pass through the disrupted blood-spinal cord barrier and localize in the lesion cavity and are significantly effective in restoring locomotors functions with a single dose whereas control animals (untreated, enzymes alone or empty NPs) remain paraplegic. Our main objectives in this proposal are both translational and basic, and are a) to demonstrate robust preclinical efficacy with Pro-NPs under clinically relevant conditions in the above animal model of SCI and b) to improve our mechanistic understanding of the treatment, particularly to determine how Pro-NPs inhibit the secondary injury cascade and promote endogenous neuronal repair mechanisms. The specific aims are: AIM 1: Delineate parameters critical for Pro-NP delivery to the lesion site. AIM 2: Determine functional recovery following treatment. AIM 3: Understand the repair mechanisms at molecular and cellular levels. If we validate our hypothesis, the most significant result of our study would be a better mechanistic understanding of neuronal repair facilitated with Pro-NPs that could also have potential impact in treating other traumatic CNS injuries.

 描述（由申请人提供）：我们设计了神经元保护性纳米颗粒（Pro-NP），其独特的成分含有抗氧化酶，可在持续一段时间内以活性形式释放。我们的目标是测试它们治疗急性脊髓损伤（SCI）的功效。 SCI 导致的残疾是一个重大的全球健康问题，主要影响年轻人 人口。美国有近 130 万人因 SCI 导致瘫痪，每年的护理费用达 405 亿美元。目前尚无有效的治疗方法可以达到 SCI 后的功能恢复。创伤性 SCI 的病理生理学涉及最初的身体冲击，从而导致退行性细胞和分子事件的继发性损伤级联。随着时间的推移，继发性损伤会沿着脊髓蔓延，这会增加新的残疾程度并产生破坏性影响。撞击部位活性氧 (ROS) 的形成是这些继发性级联损伤的重要组成部分。我们假设，有效且持续地将抗氧化剂输送到病变部位可以减轻 SCI 后氧化应激介导的退行性事件，并促进内源性神经元修复机制，从而恢复运动、神经和生理功能。在创伤性 SCI 胸部大鼠模型的初步研究中，我们证明了在 3 小时静脉内给药后。损伤后，Pro-NPs 穿过破坏的血脊髓屏障并定位在病变腔内，并且单剂量即可显着有效地恢复运动功能，而对照动物（未经治疗、单独使用酶或空 NPs）仍处于截瘫状态。我们在本提案中的主要目标是转化性和基础性的，a) 在上述 SCI 动物模型的临床相关条件下证明 Pro-NP 的强大临床前疗效，b) 提高​​我们对治疗机制的理解，特别是确定 Pro-NP 如何抑制继发性损伤级联和促进内源性神经元修复机制。具体目标是： 目标 1：描绘对 Pro-NP 递送至病变部位至关重要的参数。目标 2：确定治疗后的功能恢复情况。目标 3：了解分子和细胞水平的修复机制。如果我们验证我们的假设，我们研究的最重要结果将是对 Pro-NP 促进的神经元修复有更好的机制理解，这也可能对治疗其他创伤性中枢神经系统损伤产生潜在影响。