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: 9021013
• 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/9021013
• 关键词: Acute; Address; Affect; Aftercare; 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; Health; Inflammatory; Injury; Lesion; Leukocytes; Life; Locomotor Recovery; Mediating; Methylprednisolone; Microglia; Modeling; Molecular; Molecular Weight; Morbidity - disease rate; Muscular Atrophy; Natural regeneration; Nature; Neurologic; 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; neuron apoptosis; neuron loss; neurophysiology; neuroprotection; neutrophil; oxidative damage; preclinical efficacy; 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(申请人提供)：我们设计了神经元保护纳米颗粒(Pro-NPs)，具有独特的成分，含有抗氧化酶，在持续的一段时间内以活性形式释放。我们的目标是测试它们对治疗急性脊髓损伤(SCI)的疗效。脊髓损伤导致的残疾是一个主要的全球健康问题，主要影响年轻人。 人口。美国有近130万人因脊髓损伤而瘫痪，每年为他们的护理花费405亿美元。目前，还没有有效的治疗方法可以达到 脊髓损伤后的功能恢复。创伤性脊髓损伤的病理生理学涉及最初的物理冲击，导致退行性细胞和分子事件的继发性损伤级联反应。随着时间的推移，继发性损伤会沿着脊髓扩散，这会增加新的残疾水平，并具有毁灭性的影响。撞击部位的活性氧(ROS)生成是这些二次损伤级联反应的重要组成部分。我们推测，有效和持续地将抗氧化剂输送到损伤部位可以减轻氧化应激介导的脊髓损伤后的变性事件，并促进内源性神经元修复机制，导致运动、神经和生理功能的恢复。在创伤性脊髓损伤大鼠胸部模型的初步研究中，我们证明了在静脉注射3小时后。损伤后，Pro-NPs穿过被破坏的血脊髓屏障，定位于损伤腔内，并在单次给药后显著恢复运动功能，而对照组动物(未治疗、单独使用酶或空NPs)仍处于截瘫状态。我们在这项建议中的主要目标是翻译性和基础性的，a)在上述脊髓损伤动物模型中展示Pro-NPs在临床相关条件下的强大临床前疗效，以及b)提高我们对治疗机制的理解，特别是确定Pro-NPs如何抑制继发性损伤级联反应和促进内源性神经元修复机制。具体目标是：目标1：描述对Pro-NP输送到病变部位至关重要的参数。目的2：确定治疗后的功能恢复情况。目的3：在分子和细胞水平上了解修复机制。如果我们验证我们的假设，我们的研究最重要的结果将是更好地从机制上理解Pro-NPs促进的神经元修复，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。