Nanotechnology for Amyotrophic Lateral Sclerosis

描述（由申请人提供）：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SOD 1G 93 A小鼠模型测试新的药理学策略。这项研究使我们考虑将氧化铈（CeO 2）纳米颗粒作为缓解与ALS神经变性相关的氧化应激的有效手段。这些纳米颗粒的开发是为了减少材料科学和制造领域的自由基损伤，但直到最近才显现出其生物医学潜力。我们实验室的初步研究表明，CeO 2纳米颗粒剂量依赖性地保护培养的NSC-34运动神经元样细胞免受急性H2 O2毒性，在低纳摩尔范围内的纳米颗粒浓度。此外，纳摩尔浓度的CeO 2纳米颗粒减少蛋白质羰基化（氧化）在原代星形胶质细胞培养的新生SOD 1G 93 A小鼠，无论是在存在和不存在强加的细胞因子的挑战。最值得注意的是，初步研究表明，用CeO 2保守治疗显著减缓了SOD 1G 93 A小鼠的疾病进展并延长了存活时间。这些初步发现激发了以下特定目标，这些目标将更好地定义CeO 2纳米颗粒在SOD 1G 93 A小鼠中的生物学效应，并确定纳米颗粒是否为临床开发提供了可靠的机会。SPECIFIC AIM 1将检验全身给予CeO 2纳米颗粒可以减缓ALS的SOD 1G 93 A小鼠模型中的临床疾病进展的假设。特异性目的2将测试以下假设：全身给予CeO 2纳米颗粒可以减缓SOD 1G 93 A突变小鼠中运动神经元死亡、神经炎症和氧化应激生物标志物积累。SPECIFIC AIM 3将测试CeO 2纳米颗粒是否与全身给药的利鲁唑相互作用，以改善或减少小鼠临床结局。由于利鲁唑是目前治疗人类ALS的标准，因此在未来的人类临床试验中，停用利鲁唑可能被认为是不道德的，因此在小鼠中探索的新型ALS疗法应该在利鲁唑共同给药的背景下考虑。 公共卫生相关性：该项目将测试氧化铈纳米颗粒作为一种新的治疗工具，用于减缓肌萎缩侧索硬化症（ALS）在标准的，广泛接受的疾病小鼠模型中的进展。该项目还将测试这些纳米颗粒在ALS小鼠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.