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

• 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
• 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' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Alzheimer' 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

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.

项目概要/摘要 阿尔茨海默病 (AD) 目前影响约 620 万美国人，预计这一数字将增加至 除非找到新的治疗方法或干预措施来预防或延缓 AD 的发作，否则到 2060 年将有 1400 万人患病。 利用免疫系统来预防或消除 Aβ 和/或 tau 蛋白病理是一种有前途的疾病 - 改变治疗 AD 的治疗方法 目前，所有先前和正在进行的免疫疗法。 研究仅针对 Aβ 或 tau 蛋白的一个表位，因为大多数 AD 病例是多因素影响的。 散发性AD是由多种机制引起的，单个目标不太可能足以阻止或减少 基于 Aβ 和 tau 在 AD 发病机制中的作用，免疫治疗 同时靶向 Aβ 和 tau 的多个表位可能为 AD 药物提供一种有前途的方法 该项目的长期目标是开发一种新型、有效的 AD 疫苗。 该项目的具体目标是开发一种多价“马赛克”疫苗，称为 SNAP-AD，针对多种 Aβ 和 tau 的表位同时与自发纳米脂质体抗原颗粒 (SNAP) 平台和 为了研究其在转基因小鼠模型中治疗 AD 的效果，我们的工作假设是： 同时针对 Aβ 和 tau 的多个表位的免疫疗法是一种有前途的方法 为了检验这一新假设，我们提出了三个具体目标：(1) 配制并表征 SNAP-AD，这是一种包含三个 tau 蛋白和两个 Aβ 肽的镶嵌纳米颗粒疫苗 POP BIO 将同时针对五价 SNAP-AD 疫苗进行配制和表征。 tau 位于 1 个 N 末端区域 (Tau 6-18)、1 个中间区域 (Tau 184-195) 和 1 个 C 末端区域 (pS396/S404)， 以及N端Aβ（1-14）和N端焦谷氨酸Aβ（pE3-14），并开发了制造方法 具有可重复的批次间表征以及量化每种肽和免疫原性的方案 (2) 评估 SNAP-AD 的免疫干扰、Th1 偏向细胞反应、 神经炎症和抗体的耐久性将在 5 重中进行评估。 免疫原，如果观察到，将测试可能的分支方法，细胞反应，Th1/Th2 偏差。 将探测 SNAP-AD 诱导的抗体反应和抗体的持久性 (3) 确定 SNAP-。 使用 10 个月大的 3xTg-AD 小鼠和年龄匹配的野生型小鼠的 AD 功效。 将使用 SNAP-AD 进行免疫，并在第三次接种后一个月内加强两次，间隔为 4 周。 免疫、行为测试，包括一般行为、焦虑、运动活动和认知功能， 将进行，并通过生化/免疫组织化学方法研究 Aβ 和 tau 病理学。 拟议的研究将揭示多价免疫疗法是否具有有希望的治疗效果 该项目的积极成果可能会带来新的成果。 用于治疗 AD 的疫苗，这将改善 AD 患者的生活质量。