A new approach to immunotherapy for ALS

ALS 免疫治疗新方法

基本信息

批准号：
9808031
负责人：
ZUOSHANG XU
金额：
$ 46.06万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9808031
关键词：
Active Immunization Adjuvant Age Aging Alzheimer&apos s Disease Amyloid beta-Protein Amyotrophic Lateral Sclerosis Animal Model Antibodies Antibody Formation Antibody Response Antigens Binding Cessation of life Clinical Clinical Treatment Clinical Trials Consensus Data Disease Disease Progression Encapsulated Glucans Histocompatibility Antigens Class II Human Huntington Disease Immune response Immunization Immunosuppressive Agents Immunotherapy In Vitro Lead Massachusetts Modernization Monitor Motor Neurons Mus Nerve Degeneration Nervous system structure Neuraxis Neurodegenerative Disorders Neurons Paralysed Parkinson Disease Passive Immunization Pathogenicity Patients Proteins Public Health Regulatory T-Lymphocyte Reporting Research Senile Plaques Series Sirolimus Societies Testing Therapeutic Therapy Clinical Trials Toxic effect Transgenic Mice Treatment Efficacy Universities Vaccinated Vaccines alpha synuclein base brain dysfunction clinical efficacy medical schools misfolded protein motor disorder mouse model mutant neuroinflammation neuron loss neuropathology novel novel strategies novel therapeutics novel vaccines particle pre-clinical prevent protein aggregate protein aggregation protein misfolding response superoxide dismutase 1 synucleinopathy theories therapeutic vaccine vaccination strategy vaccine candidate

项目摘要

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.

项目概要 ALS 是一种毁灭性的致命疾病。目前没有任何治疗方法可以阻止或逆转这种病。目前的科学共识表明，这种神经退行性疾病和其他神经退行性疾病疾病是由中枢神经中有毒蛋白质聚集体的积累引起的系统。因此，清除这些蛋白质聚集物可能会实现减慢、停止或扭转这些疾病的进展。该提案将测试一种新型主动疫苗接种两种小鼠模型分别表达突变型 SOD1 和突变型 PFN1 的 ALS 策略。该策略采用由错误折叠的致病蛋白和雷帕霉素封装在葡聚糖微粒中。这一新策略的主要优势在于先前建立的方法是其触发强大的体液免疫的能力针对突变蛋白的反应，同时包含有害的神经炎症与针对错误折叠蛋白质的免疫反应有关。我们预测这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，清除蛋白质聚集物，从而中和突变蛋白质的毒性不会引发神经炎症。最终我们相信这些影响将导致临床益处包括减缓或阻止疾病。如果这些预测成为现实，我们将有一种新的有效候选疫苗可以进入治疗 ALS 的临床试验。