A Single-cell Platform for Analyzing the Peripheral Immune Response in Alzheimer’s and Alzheimer’s Related Diseases

用于分析阿尔茨海默病和阿尔茨海默病相关疾病的外周免疫反应的单细胞平台

• 批准号: 10010944
• 负责人: Timothy S McConnell
• 金额: $ 99.96万
• 依托单位: ISOPLEXIS, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-15 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10010944
• 关键词: Affect; Age; Alzheimer' s Disease; Alzheimer' s disease related dementia; Antibodies; Automation; Bar Codes; Biological Assay; Biological Markers; Blinded; Blood Cells; Blood specimen; CD8-Positive T-Lymphocytes; Cells; Cerebrospinal Fluid; Clinical; Communication; Comparative Study; Dementia; Detection; Development; Devices; Diagnosis; Disease; Disease Progression; Early Diagnosis; Evaluation; Frontotemporal Dementia; Goals; Human; Immune; Immune response; Immune system; Immunotherapy; Industry; Inflammation; Inflammatory; Inflammatory Response; Influentials; Legal patent; Longitudinal Studies; Malignant Neoplasms; Measurable; Measurement; Measures; Molecular Target; Monitor; Multiple Sclerosis; Neuraxis; Neurodegenerative Disorders; Neurons; Outcome; Patients; Performance; Peripheral; Phase; Predictive Value; Preparation; Protein Secretion; Proteins; Proteomics; Publishing; Recording of previous events; Research; Research Personnel; Resolution; Role; Sampling; System; T cell response; T-Lymphocyte; Technology; Testing; Therapeutic; Time; base; behavioral variant frontotemporal dementia; blind; blood-based biomarker; cell type; cytokine; improved; indexing; instrument; miniaturize; monocyte; multiple sclerosis patient; neuroinflammation; optimal treatments; peripheral blood; protein biomarkers; response; response biomarker; side effect; success; user-friendly

With this Phase II submission, IsoPlexis will develop an automated system to evaluate the combined peripheral immune response of T cells and monocyte cells to differentiate and monitor neurodegenerative diseases (ND) including Alzheimer’s (AD), Frontotemporal Dementia (FTD), and Multiple Sclerosis (MS). Monitoring disease progression and treatment impact on the immune response currently requires risky Cerebral Spinal Fluid sampling. However, the communication between the central and peripheral immune systems exists and we show it requires a sophisticated single-cell detection system to decipher these interactions from a blood sample. The limited success of current ADRD treatments has led to two key observations: (1) targeting molecular contributors to disease without impacting the inflammatory response or disease progression, or (2) immunotherapy targeting not providing measurably productive outcomes and inducing unfavorable inflammatory side effects. Multiplexed protein biomarkers have proven critical in other human immune therapies (e.g., cancer), drastically improving clinical success and inspiring the extension of this technology towards ADRD. Developing such biomarkers for ADRD requires a technology that (1) measures secreted protein polyfunctionality in a single- cell platform classified by subsets of ADRD peripheral blood cells, (2) isolates sensitive peripheral immune cells necessary to establish correlative biomarker disease profiles, and (3) is able to monitor these emerging biomarkers upon treatment. The IsoPlexis IsoCode’s polyfunctional strength index (PSI), using 30+ secreted proteins per T-cell, has proven to be a correlate of objective response in multiple types of immunotherapies. In a published study on MS patient samples, the IsoPlexis platform has demonstrated a strong stimulatory and inflammatory cytokine secretion profile from monocytes, compared to that of healthy donors, and this secretion profile is greatly reduced upon successful treatment. Initial studies of AD peripheral T cells have shown an increased inflammatory profile relative to age-matched donors driven by unique polyfunctional subsets. With a unique focus on the ND market need, we wish to transition this technology into a fully viable commercial, automated assay system to greatly expedite the industry’s development of ADRD therapies. This Phase II plan enables beta-testing in clinical settings with strong scientific performance history. Aim 1: Develop an automated “flow cell” consumable compartment, which captures ADRD monocytes and T cells in parallel and measures 32- plex single-cell cytokine secretions. Aim 2: Produce a miniaturized, benchtop automated flow cell analysis and workflow system, with cell enrichment module, to provide clinical labs user-friendly sample to answer format. Aim 3: Demonstrate proof-of-concept ability to use IsoPlexis automation at UCI, UCSF and UCONN trials and to profile polyfunctional response of peripheral immune cells in a comparative study of neurodegenerative diseases.

通过本次II期申报，IsoPlexis将开发一个自动化系统，以评估组合的外周血管 T细胞和单核细胞免疫应答对神经退行性疾病（ND）的鉴别和监测 包括阿尔茨海默病（AD）、额颞叶痴呆（FTD）和多发性硬化症（MS）。监测疾病 疾病进展和治疗对免疫反应的影响目前需要有风险的脑脊液 取样.然而，中枢和外周免疫系统之间的沟通是存在的， 表明它需要一个复杂的单细胞检测系统来破译血液样本中的这些相互作用。 目前ADRD治疗的有限成功导致了两个关键观察结果：（1）靶向分子靶向， 不影响炎症反应或疾病进展的疾病贡献者，或（2） 免疫治疗靶向不提供可测量的生产性结果并诱导不利的炎性反应 副作用.多重蛋白质生物标志物已被证明在其他人类免疫疗法中至关重要（例如，癌症）， 极大地提高了临床成功率，并激发了该技术向ADRD的延伸。发展中 ADRD的这种生物标志物需要一种技术，该技术（1）在单个- 通过ADRD外周血细胞亚群分类的细胞平台，（2）分离敏感的外周免疫细胞 必须建立相关的生物标志物疾病概况，和（3）能够监测这些新出现的 生物标志物。IsoPlexis IsoCode的多功能强度指数（PSI），使用30+分泌 已经证明，每个T细胞的蛋白质数量与多种类型的免疫疗法中的客观应答相关。在 一项已发表的关于MS患者样本的研究，IsoPlexis平台已证明具有强刺激性， 与健康供体相比，来自单核细胞的炎性细胞因子分泌谱，并且这种分泌 在成功治疗后，轮廓大大减小。对AD外周T细胞的初步研究表明， 相对于年龄匹配的供体，炎症特征增加，这是由独特的多功能亚群驱动的。与 我们专注于ND市场需求，我们希望将这项技术转变为完全可行的商业化， 自动化检测系统，大大加快了ADRD疗法的行业发展。第二阶段计划 能够在具有强大科学性能历史的临床环境中进行β测试。目标1：开发自动化 “流动池”消耗性隔室，其平行捕获ADRD单核细胞和T细胞，并测量32- 40 μ g/ml。 复合单细胞细胞因子分泌。目标2：生产小型化、台式自动化流动池分析， 工作流程系统，具有细胞富集模块，为临床实验室提供用户友好的样本答案格式。 目标3：展示在UCI、UCSF和UCONN试验中使用IsoPlexis自动化的概念验证能力，并 在神经退行性疾病的比较研究中描绘外周免疫细胞的多功能应答。