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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.

项目摘要肌萎缩侧索硬化症是一种毁灭性且致命的疾病。目前还没有可以停止或逆转的治疗方法。这种病。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中枢神经中有毒的蛋白质聚集体聚集引起的。系统。因此，清除这些蛋白质聚集体可能会减慢、停止或逆转这些疾病的发展。这项提议将测试一种新的活性疫苗接种分别表达突变型SOD1和突变型PFN1的两种ALS小鼠模型的策略。这种策略使用的疫苗是由错误折叠的致病蛋白和雷帕霉素被包裹在葡聚糖微粒中。这一新战略的主要优势是以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，同时抑制有害的神经炎症与对错误折叠的蛋白质的免疫反应有关。我们预测这一点疫苗将提高针对错误折叠和聚集的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好处包括延缓或阻止疾病。如果这些预测成为现实，我们将有一种新的有效疫苗候选进入治疗ALS的临床试验。