A new approach to immunotherapy for ALS

项目摘要 ALS是一种毁灭性的致命疾病。目前还没有治疗方法可以阻止或逆转 这种疾病。目前的科学共识表明，这种和其他神经退行性疾病 疾病是由有毒蛋白质聚集物在中枢神经系统中的积累引起的 系统因此，清除这些蛋白质聚集体可以实现减缓、停止或减少蛋白质聚集体的形成。 逆转这些疾病的发展。这项提案将测试一种新型主动疫苗 在两种分别表达突变体SOD1和突变体PFN1的ALS小鼠模型中， 该策略采用由错误折叠的致病蛋白组成的疫苗， 包封在葡聚糖微粒中的雷帕霉素。这一新战略的主要优势在于， 先前建立的方法是它能够触发强大的体液免疫， 对突变蛋白的反应，同时含有有害的神经炎症 与针对错误折叠蛋白质的免疫反应相关。我们预测这一 疫苗将提高针对错误折叠和聚集突变体的高水平抗体 蛋白质，清除蛋白质聚集体，从而中和突变蛋白质的毒性 而不会引发神经炎症最终，我们相信这些影响将导致临床 包括减缓或阻止疾病。如果这些预测实现， 有一个新的有效的候选疫苗进入临床试验治疗ALS。

Project Summary ALS is a devastating and fatal disease. At present there is no treatment that can halt or reverse this disease. Current scientific consensus indicates that this and other neurodegenerative diseases are caused by the accumulation of toxic protein aggregates in the central nervous system. Therefore, clearing these protein aggregates may achieve slowing down, halting or reversing the progression of these diseases. This proposal will test a novel active vaccination strategy in two mouse models for ALS expressing mutant SOD1 and mutant PFN1, respectively. This strategy employs vaccines that are composed of the misfolded pathogenic proteins and rapamycin encapsulated in glucan microparticles. The key advantage of this new strategy over the previously established approaches is its capability in triggering a robust humoral immune response against the mutant protein while containing the detrimental neuroinflammation associated with the immune response against the misfolded proteins. We predict that this vaccine will raise high levels of antibodies against the misfolded and aggregated mutant proteins, clear the protein aggregates and thereby neutralize the mutant proteins' toxicity without triggering neuroinflammation. Ultimately we believe these effects will lead to clinical benefit including slowing down or halting the disease. If these predictions are realized, we will have a new efficacious vaccine candidate to move forward into clinical trial for treatment of ALS.