Mosaic Display of Multivalent Tau and A-Beta peptides on Immunogenic SNAP Liposomes

多价 Tau 和 A-Beta 肽在免疫原性 SNAP 脂质体上的马赛克展示

基本信息

批准号：
10699370
负责人：
Chunling Dai
金额：
$ 24.89万
依托单位：
POP BIOTECHNOLOGIES, INC
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-15 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10699370
关键词：
3xTg-AD mouse Affect Age Alzheimer Vaccines Alzheimer&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos s disease related dementia Alzheimer&apos s disease therapeutic American Amyloid beta-Protein Animals Antibodies Antibody Response Antigens Anxiety Basic Science Behavior Biochemical Biotechnology Brain C-terminal COVID-19 vaccine Clinical Trials Collaborations Dementia Developmental Disabilities Disease Dose Drug Kinetics Epitopes Etiology Exhibits Goals Health Human Immune Immune System Diseases Immune system Immunization Immunize Immunotherapy Impaired cognition Individual Institution Intervention Lipids Liposomes Methods Motor Activity Mus N-terminal Nature Neurofibrillary Tangles New York Outcome Pathogenesis Pathology Peptides Pharmaceutical Preparations Phase Phase II Clinical Trials Preventive Proteins Protocols documentation Pyroglutamate Quality of life Reproducibility Research Rodent Model Role Safety Senile Plaques Societies Surface System Technology Testing Therapeutic Therapeutic Effect Transgenic Mice Vaccines Wild Type Mouse abnormally phosphorylated tau behavior test cognitive function drug development extracellular immunogenic improved innovation manufacture mosaic mouse model nanoliposome nanoparticle neuroinflammation new therapeutic target novel novel vaccines particle phase 1 study phase 3 testing preclinical study prevent response tau Proteins therapeutic target therapeutic vaccine therapeutically effective vaccine development

项目摘要

Project Summary/Abstract Alzheimer’s disease (AD) currently affects ~6.2 million Americans, and this number is projected to increase to 14 million by 2060 unless novel treatments or interventions to prevent or delay the onset of AD are identified. Harnessing the immune system to prevent or remove Aβ and/or tau pathologies represents a promising disease- modifying therapeutic approach for the treatment of AD. Currently, all the previous and ongoing immunotherapy studies target only one epitope of either Aβ or tau protein. Because most AD cases are multifactorial, and sporadic AD is caused by multiple mechanisms, it is unlikely that a single target will be sufficient to stop or reduce the progression of AD. Based on the role of Aβ and tau in the pathogenesis of AD, immunotherapy simultaneously targeting multiple epitopes of both Aβ and tau may present a promising approach for AD drug development. The long-term objective of the proposed project is to develop a novel, effective vaccine for AD. The specific goal of this project is to develop a multivalent "mosaic" vaccine, termed SNAP-AD, targeting multiple epitopes of Aβ and tau simultaneously with the spontaneous nanoliposome antigen particle (SNAP) platform and to investigate its therapeutic effects for treating AD in a transgenic mouse model. Our working hypothesis is that immunotherapy simultaneously targeting the multiple epitopes of both Aβ and tau is a promising approach for developing effective AD therapeutics. To test this novel hypothesis, we propose three specific aims: (1) Formulate and characterize SNAP-AD, a mosaic nanoparticle vaccine comprising three tau and two Aβ peptide epitopes. POP BIO will formulate and characterize the pentavalent SNAP-AD vaccine simultaneously targeting tau at one N-terminal region (Tau 6-18), one mid-region (Tau 184-195), and one C-terminal region (pS396/S404), as well as N-terminal Aβ (1-14) and N-terminal pyroglutamate Aβ (pE3-14), and develop a manufacturing method with reproducible batch-to-batch characterization and the protocols to quantify each peptide and immunogenic lipid component. (2) Assess SNAP-AD for immune interference, Th1-biased cellular response, neuroinflammation, and antibodies’ durability. Immune interference will be assessed amongst the 5-plex immunogens, and if observed, possible ramification methods will be tested. Cellular responses, Th1/Th2 bias of the antibody response, and the antibodies’ durability induced by SNAP-AD will be probed. (3) Determine SNAP- AD efficacy using the 3xTg-AD mouse model. Ten-month-old 3xTg-AD mice and age-matched wild-type mice will be immunized with SNAP-AD and boosted twice with a four-week interval. One month after the third dose of immunization, behavioral tests, including general behavior, anxiety, locomotor activity, and cognitive function, will be conducted, and Aβ and tau pathology will be investigated both biochemically/immunohistochemically. The proposed studies will reveal whether the multivalent immunotherapy approach has promising therapeutic effects on AD pathologies and cognitive impairment. A positive outcome of this project would potentially lead to a novel vaccine for the treatment of AD, which will improve the quality of life of individuals with AD.

项目摘要/摘要阿尔茨海默氏病（AD）目前影响约620万美国人，预计这一数字将增加到到2060年，除非确定预防或延迟AD发作的新型治疗或干预措施，否则1400万。利用免疫系统预防或去除Aβ和/或TAU病理代表有希望的疾病 - 修改AD治疗的治疗方法。目前，所有以前的免疫疗法研究仅针对Aβ或TAU蛋白的一集。因为大多数AD案例都是多因素的，并且零星广告是由多种机制引起的，单个目标不足以停止或减少 AD的进展。根据Aβ和TAU在AD发病机理中的作用，免疫疗法类似地，靶向Aβ和TAU的多个表位可能会呈现出有希望的AD药物的方法发展。拟议项目的长期目标是开发一种新型的有效疫苗作为AD。该项目的具体目标是开发一种多价“马赛克”疫苗，称为SNAP-AD，针对多个 Aβ和Tau的表位简单地使用赞助的纳米脂体抗原颗粒（SNAP）平台和研究其在转基因小鼠模型中治疗AD的治疗作用。我们工作的假设是免疫疗法仅针对Aβ和TAU的多个表位是一种有前途的方法开发有效的广告疗法。为了检验这个新的假设，我们提出了三个具体目标：（1）配方和表征Snap-AD，一种镶嵌纳米颗粒疫苗，其中包括三个tau和两种Aβ肽表位。 Pop Bio将制定并表征五价SNAP-AD疫苗，而简单地靶向在一个N末端区域（Tau 6-18），一个中区（Tau 184-195）和一个C末端区域（PS396/S404），一个中部区域（Tau 6-18），一个Tau 以及N末端Aβ（1-14）和N末端焦谷氨酸Aβ（PE3-14），并开发一种制造方法具有可再现的批处理表征以及量化每种肽和免疫原性的方案脂质成分。（2）评估SNAP-AD的免疫寻求，Th1偏见的细胞反应，神经炎症和抗体的耐用性。免疫干扰将在5 plex中评估免疫原子，如果观察到可能的分支化方法。细胞反应，Th1/Th2偏差将探测抗体反应和SNAP-AD引起的抗体的耐用性。（3）确定snap- 使用3XTG-AD鼠标模型的广告效率。十个月大的3XTG-AD小鼠和年龄匹配的野生型小鼠将用SNAP-AD免疫，并以四周的间隔进行两次增强。第三剂剂量后一个月免疫，行为测试，包括一般行为，动画，运动活动和认知功能，将进行，Aβ和TAU病理将在生化/免疫组织化学上进行研究。拟议的研究将揭示多价免疫疗法方法是否有望产生治疗作用关于AD病理和认知障碍。该项目的积极结果可能会导致新颖用于治疗AD的疫苗，这将改善AD患者的生活质量。