Nanotechnology for Amyotrophic Lateral Sclerosis

描述（由申请人提供）：我们实验室一直在研究肌萎缩性侧索硬化症（ALS）治疗干预的潜在靶点，使用SOD1G93A小鼠模型来测试新的药物策略。这项研究使我们考虑氧化铈纳米颗粒作为一种有效的手段来减轻与ALS神经退行性变相关的氧化应激。这些纳米颗粒是为了减少材料科学和制造领域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，CeO2纳米颗粒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。此外，纳米摩尔浓度的CeO2纳米颗粒在存在和不存在细胞因子刺激的情况下，都能减少新生SOD1G93A小鼠培养的原代星形胶质细胞的蛋白质羰基化（氧化）。最值得注意的是，初步研究表明，在SOD1G93A小鼠中，CeO2保守治疗显著减缓了疾病进展并延长了生存期。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CeO2纳米颗粒在SOD1G93A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将在SOD1G93A ALS小鼠模型中验证系统给予CeO2纳米颗粒可以减缓临床疾病进展的假设。SPECIFIC AIM 2将验证系统给药CeO2纳米颗粒可以减缓SOD1G93A突变小鼠的运动神经元死亡、神经炎症和氧化应激生物标志物积累的假设。SPECIFIC 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。由于利鲁唑是目前治疗人类ALS的标准药物，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，在利鲁唑联合给药的情况下，应该考虑在小鼠身上探索新的ALS治疗方法。

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.