Neuronal Protective Nanoparticles for Treating Acute SCI

 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），其具有独特的组合物，含有在持续时间内以活性形式释放的抗氧化酶。我们的目标是测试它们治疗急性脊髓损伤（SCI）的疗效。SCI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SCI而瘫痪，每年的护理费用为405亿美元。目前还没有有效的治疗方法可以达到 SCI后的功能恢复创伤性SCI的病理生理学包括最初的物理冲击，其导致退化的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扩散，这会增加新的残疾程度，并产生破坏性影响。在撞击部位形成活性氧是这些继发性损伤级联的重要组成部分。我们假设，有效和持续的抗氧化剂输送到病变部位可以抑制氧化应激介导的退行性事件后SCI和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。在胸部创伤性SCI大鼠模型的初步研究中，我们证明了在损伤后3小时静脉内给药后，Pro-NP穿过破坏的血-脊髓屏障并定位在病变腔中，并且用单剂量在恢复运动功能方面显著有效，而对照动物（未处理的、单独的酶或空NP）保持截瘫。我们在该提案中的主要目的是转化和基本的，并且是a）在上述SCI动物模型中在临床相关条件下证明Pro-NP的稳健的临床前功效，和B）提高我们对治疗的机制理解，特别是确定Pro-NP如何抑制继发性损伤级联并促进内源性神经元修复机制。具体目标为：目标1：描述Pro-NP输送至病变部位的关键参数。目的2：确定治疗后的功能恢复。目的3：从分子和细胞水平了解损伤修复机制.如果我们验证了我们的假设，我们研究的最重要的结果将是更好地理解Pro-NP促进的神经元修复的机制，这也可能对治疗其他创伤性CNS损伤产生潜在影响。

 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.