Nanotechnology for Amyotrophic Lateral Sclerosis

描述(申请人提供)：我们的实验室一直在研究肌萎缩侧索硬化症(ALS)治疗干预的潜在靶点，使用SOD1G93A小鼠模型来测试新的药理策略。这项研究使我们认为CeO2纳米颗粒是缓解与ALS神经变性相关的氧化应激的有效手段。这些纳米粒子是为了减少材料科学和制造领域中的自由基损伤而开发的，但直到最近，它们的生物医学潜力才变得明显。我们实验室的初步研究表明，纳米CeO2在低纳摩尔浓度范围内对培养的NSC-34运动神经元样细胞具有剂量依赖性的保护作用，使其免受H_2O_2的急性毒性。此外，纳米浓度的CeO2纳米颗粒减少了SOD1G93A新生小鼠原代培养的星形胶质细胞的蛋白质羰化(氧化)，无论存在还是不存在强加的细胞因子挑战。最值得注意的是，初步研究表明，CeO2保守治疗显著减缓了SOD1G93A小鼠的疾病进展和延长了存活时间。这些初步发现激发了以下具体目标，将更好地定义CeO2纳米颗粒在SOD1G93A小鼠中的生物效应，并确定纳米颗粒是否为临床开发提供了可信的机会。在ALS的SOD1G93A小鼠模型中，特定的AIM 1将测试系统地给药CeO2纳米颗粒可以减缓临床疾病进展的假设。特定的AIM 2将测试系统给予CeO2纳米颗粒可以减缓SOD1G93A突变小鼠运动神经元死亡、神经炎症和氧化应激生物标记物积累的假设。特定的AIM 3将测试CeO2纳米颗粒是否与全身给药的利鲁唑相互作用，以改善或减少小鼠的临床结果。由于利鲁唑是目前人类肌萎缩侧索硬化症的治疗标准，在未来的人类临床试验中，不使用利鲁唑可能被认为是不道德的，因此在小鼠身上探索的新的肌萎缩侧索硬化症治疗方法应该在利鲁唑联合给药的背景下考虑。 与公共卫生相关：该项目将在标准的、被广泛接受的肌萎缩侧索硬化症(ALS)小鼠模型中测试氧化铈纳米颗粒作为一种新的治疗工具来减缓肌萎缩侧索硬化症(ALS)的进展。该项目还将测试这些纳米颗粒在ALS小鼠的中枢神经系统中作为催化抗氧化剂的能力。

DESCRIPTION (provided by applicant): Our laboratory has been researching potential targets for therapeutic intervention in amyotrophic lateral sclerosis (ALS), using the SOD1G93A mouse model to test new pharmacologic strategies. This research has led us to consider cerium oxide (CeO2) nanoparticles as a potent means to mitigate oxidative stress associated with ALS neurodegeneration. These nanoparticles were developed to reduce free radical damage in the fields of materials science and manufacturing, but only recently has their biomedical potential become evident. Preliminary studies from our laboratory indicate that CeO2 nanoparticles dose-dependently protect cultured NSC-34 motor neuron-like cells from acute H2O2 toxicity, at nanoparticle concentrations in the low nanomolar range. Furthermore, nanomolar concentrations of CeO2 nanoparticles reduced protein carbonylation (oxidation) in primary astrocytes cultured from neonatal SOD1G93A mice, both in the presence and the absence of an imposed cytokine challenge. Most remarkably, preliminary studies suggest that conservative treatment with CeO2 remarkably slowed disease progression and prolonged survival in the SOD1G93A mouse. These preliminary findings motivate the following SPECIFIC AIMS that will better define the biological effects of CeO2 nanoparticles in the SOD1G93A mouse and ascertain whether nanoparticles offer a credible opportunity for clinical development. SPECIFIC AIM 1 will test the hypothesis that systemically administered CeO2 nanoparticles can slow clinical disease progression in the SOD1G93A mouse model of ALS. SPECIFIC AIM 2 will test the hypothesis that systemically administered CeO2 nanoparticles can slow motor neuron death, neuroinflammation, and oxidative stress biomarker accumulation in the SOD1G93A mutant mouse. SPECIFIC AIM 3 will test whether CeO2 nanoparticles interact with systemically administered riluzole to either improve or diminish murine clinical outcomes. Because riluzole is the current standard of care for human ALS, withholding of riluzole probably would be considered unethical in future human clinical trials, so that novel ALS therapies being explored in mice ought to be considered in the context of riluzole co- administration. PUBLIC HEALTH RELEVANCE: This project will test cerium oxide nanoparticles as a new therapeutic tool for slowing the progression of amyotrophic lateral sclerosis (ALS) in a standard, widely accepted mouse model for the disease. The project also will test the ability of these nanoparticles to act as catalytic antioxidants in the central nervous system of ALS mice.