Development of Blood-based Circular RNA Biomarkers for Alzheimer's Disease

开发基于血液的阿尔茨海默氏病环状 RNA 生物标志物

• 批准号: 10480165
• 负责人: Julie Collens
• 金额: $ 50.85万
• 依托单位: VIVID GENOMICS, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10480165
• 关键词: Address; Adopted; Advanced Development; Age of Onset; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease related dementia; Alzheimer’s disease biomarker; Amyloid beta-Protein; Biological Markers; Blood; Blood specimen; Brain; Brain Pathology; Cerebrospinal Fluid; Cessation of life; Clinical; Clinical Trials; Clinical Trials Design; Collaborations; Collection; Development; Diagnosis; Disease; Disease Progression; Foundations; Future; Genetic; Genomic DNA; Genomics; Image; Immunoprecipitation; Individual; Machine Learning; Measures; Methods; Modeling; Monitor; National Institute of Neurological Disorders and Stroke; National Institute on Aging; Nature; Neurosciences; Pathologic; Patients; Pattern; Phase; Public Health; Reporting; Research; Saliva; Severities; Small Business Innovation Research Grant; Symptoms; Testing; Therapeutic; Time; Transcript; Treatment Efficacy; Universities; Validation; Washington; Work; base; blood-based biomarker; case control; circular RNA; cohort; commercialization; cost effective; design; differential expression; disease diagnosis; follow-up; genetic testing; high risk; insight; interest; minimally invasive; neuroimaging; novel; predictive modeling; recruit; response; routine practice; routine screening; screening; sex; success; tau-1; tool; trait; transcriptome sequencing

PROJECT SUMMARY—This Phase I application targets PAS-19-316 to address the priorities for a) new, cost- effective, minimally-invasive biomarkers that could be used for screening and b) research that would identify new biomarkers that could serve as surrogate measures for disease progression in Alzheimer’s Disease and Related Dementias (AD/ADRD). Specifically, Vivid Genomics is exploring the use of circular RNAs (circRNAs) in blood as a biomarker of AD and AD progression, including the possible identification of presymptomatic AD. The enormous public health challenge of AD is complicated by the lack of accessible, non-invasive tools for definitively diagnosing the disease prior to death. Although imaging and AD biomarkers in cerebrospinal fluid (CSF) can provide insight into disease status, they are not ideal for routine screening. Recently reported blood- based screens for amyloid b and phosphorylated tau (p-tau) represent a significant advance, but they require methods that are not easily scalable or may not have adequate sensitivity in early disease. In addition, they assess the presence of amyloid b and p-tau at a particular point in time and cannot currently be used to indicate the rate of disease progression or future likelihood of decline. Thus, developing new scalable, cost-effective, minimally-invasive blood-based biomarkers could provide a much-needed tool for routine screening in high-risk individuals, routine follow-up to track AD progression, or ongoing monitoring to assess treatment efficacy. Recent findings indicate several circRNAs differentially expressed in the brains of patients with and without AD are significantly associated with AD diagnosis, clinical severity, and neuropathological severity. In addition, changes in circRNA expression can be detected even in presymptomatic patients. Preliminary studies indicate these markers are also differentially expressed in blood, providing a basis for exploring blood-based circRNAs as biomarkers of AD and/or AD progression. In this proof-of-concept Phase I SBIR, Vivid proposes to identify multiple circRNAs whose expression in blood is associated with AD diagnosis, clinical severity, and/or neuro- pathological severity. Aim. Identify blood-based circRNAs that are associated with AD status and AD- biomarker positivity. RNA-seq will be used to analyze circRNAs in blood from 300 patients in the Knight Alzheimer's Disease Research Center cohort. A rank-ordered list of circRNAs of interest will be developed based on the strength of their association with AD traits adjusted for median transcript integrity score, age of onset, batch, sex, and genetic ancestry. Associations and rank order will then be validated in blood from 300 patients in the AD Neuroimaging Initiative (ADNI) cohort. Go/No-Go Criterion: Identify ≥ 2 blood-based circRNAs correlated with one or more AD traits (FDR < 0.05). Impact—Proof-of-concept would provide a foundation for development of blood-based circRNAs as biomarkers of AD and/or AD progression. Validation and regulatory clearance would provide a scalable, cost-effective, minimally-invasive alternative to current biomarkers, which could support routine screening of high-risk individuals and inform treatment decisions and clinical trial designs.

项目摘要-此第一阶段申请的目标是PAS-19-316，以解决以下优先事项：)新的、成本- 有效、微创的生物标志物，可用于筛查和b)研究，将识别新的 可作为阿尔茨海默病及相关疾病进展的替代指标的生物标志物 痴呆症(AD/ADRD)。具体来说，Vivid基因组公司正在探索在血液中使用环状RNA(CircRNAs) 作为AD和AD进展的生物标志物，包括可能识别的症状前AD。这个 AD的巨大公共卫生挑战因缺乏可获得的、非侵入性的工具而复杂化 在死前明确诊断疾病。尽管脑脊液中的影像和AD生物标志物 脑脊液(CSF)可以提供对疾病状态的洞察，但它们不是常规筛查的理想选择。最近报道的血液- 基于淀粉样蛋白b和磷酸化tau(p-tau)的筛查是一项重大的进步，但它们需要 方法不易扩展或在早期疾病中可能没有足够的敏感性。此外，他们还 评估特定时间点淀粉样蛋白b和p-tau的存在，目前不能用来指示 疾病进展的速度或未来下降的可能性。因此，开发新的可扩展、经济高效的 基于血液的微创生物标志物可以为高危患者的常规筛查提供急需的工具 个人、追踪AD进展的常规跟踪，或评估治疗效果的持续监测。近期 研究结果表明，在AD患者和非AD患者的大脑中有几个差异表达的CircRNA 与阿尔茨海默病的诊断、临床严重程度和神经病理严重程度显著相关。此外，变化 在CircRNA中，即使在症状前期的患者中也可以检测到RNA的表达。初步研究表明这些 标志物在血液中也有不同的表达，为探索基于血液的CircRNAs提供了基础 AD和/或AD进展的生物标志物。在此概念验证阶段I SBIR中，Vivid建议确定 多种CircRNA在血液中的表达与AD的诊断、临床严重程度和/或神经细胞- 病理性的严重性。瞄准。识别与AD状态和AD相关的基于血液的CircRNA 生物标记物阳性。Rna-seq将用于分析骑士医院300名患者血液中的CircRNA 阿尔茨海默病研究中心队列。感兴趣的CircRNA的排序列表将基于 根据它们与阿尔茨海默病特征的关联程度，调整了中位数成绩单完整性分数、发病年龄、 批次、性别和基因血统。然后将在300名患者的血液中验证关联性和排名顺序 在AD神经成像倡议(ADNI)队列中。通过/不通过标准：识别≥2基于血液的CircRNA 与一个或多个AD特征相关(FDR&lt；0.05)。概念的影响验证将为 以血液为基础的CircRNA作为AD和/或AD进展的生物标记物的发展。验证和监管 Clear将为目前的生物标记物提供一种可扩展、成本效益高、微创的替代方案， 可以支持对高危个体的常规筛查，并为治疗决定和临床试验设计提供信息。