Validation of a salivary miRNA diagnostic test for autism spectrum disorder

自闭症谱系障碍唾液 miRNA 诊断测试的验证

基本信息

批准号：
9898174
负责人：
Randall L Carpenter
金额：
$ 33万
依托单位：
QUADRANT BIOSCIENCES, INC.
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：
2019-06-15 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9898174
关键词：
3 year old Adaptive Behaviors Adopted Affect Age Algorithms American Anoxic Encephalopathy Autopsy Behavior Biological Markers Biological Process Biological Sciences Blood Brain Cells Characteristics Child Clinical Clinical Trials Collection Communication Communities Consumption DNA Sequence Alteration Data Detection Development Developmental Delay Disorders Diagnosis Diagnostic Diagnostic Procedure Diagnostic tests Early Intervention Early treatment Electroencephalography Elements Enrollment Ensure Environmental Risk Factor Epigenetic Process Etiology Exhibits Eye Family Future Gene Expression Genes Genetic Genetic Materials Genetic Risk Genetic Transcription Genomics Geography Goals Grant Heterogeneity Hormonal Human Human Microbiome Incidence Individual Knowledge Lead Learning Leukocytes Link Magnetic Resonance Imaging Measurement Measures Medical Methodology Methods MicroRNAs Microbe Mitochondria Modeling Monitor Neuraxis Neurodevelopmental Deficit Neurologic Neuropsychology Only Child Outcome Oxidative Stress Pain Patient Care Patient-Focused Outcomes Patients Performance Peripheral Pharmaceutical Preparations Phase Phenotype Prevalence Primary Care Physician Process Public Health RNA RNA Degradation Research Saliva Salivary Sampling Screening procedure Sensitivity and Specificity Small Business Technology Transfer Research Social Interaction Socialization Societies Specialist Specificity Stimulus Symptoms Techniques Technology Testing Therapeutic Therapeutic Intervention Time Tissues Toddler Training United States Untranslated RNA Validation Work accurate diagnosis autism diagnostic observation schedule autism spectrum disorder autistic children biomarker identification brain tissue clinical practice cohort combinatorial commercialization diagnostic accuracy diagnostic biomarker differential expression endophenotype exosome extracellular functional outcomes improved insight interest microbial community microbiota microvesicles minimally invasive multiple omics neurodevelopment next generation sequencing peer phase 1 study phase 2 study primary outcome prognostic programs prospective response secondary outcome standard of care symptom management tool trait treatment response

项目摘要

Autism spectrum disorder (ASD) is a continuum of neurodevelopmental characteristics that includes deficits in communication and social interaction, as well as restrictive, repetitive interests and behaviors. ASD is an increasing public health concern, with about 1 in 45 American children diagnosed with ASD in 2014, a 10-fold increase in prevalence over the past 40 years. The effect of ASD on both society and the economy is a large burden, estimated at more than $286 billion per year in the U.S. alone. While a single direct link to ASD diagnosis has not been determined, studies have identified genetic, epigenetic, neurological, hormonal, and environmental factors that affect outcomes for patients with ASD. In order to effectively treat patients with ASD, timely detection is crucial for implementation of early treatment options. Using knowledge of these preexisting factors for ASD, doctors can begin treatment while the patient is still young, even if the child has not begun to exhibit typical ASD symptoms. Studies suggest that earlier treatment results in better functional outcomes and reductions in symptoms of ASD. These models, medications and programs have proven to be effective in managing the symptoms of ASD, and may remove some patients from the ASD spectrum entirely. Unfortunately, current diagnostic methods for ASD are not very accurate for young children; the average age of diagnosing ASD is three years old, and about half of those are false positives. Development of accurate diagnostic biomarkers for ASD would thus represent a valuable addition to patient care. Quadrant Biosciences is developing an approach to diagnose ASD by measuring brain-related and other ribonucleic acids (micro, circular, and bacterial) in saliva. Extracellular transport of miRNA via exosomes and other microvesicles is an established epigenetic mechanism for cells to alter gene expression in nearby cells. This has enabled Quadrant to measure genetic material that may have originated from the central nervous system simply by collecting saliva. This method minimizes many of the limitations associated with analysis of post-mortem brain tissue (e.g., anoxic brain injury, RNA degradation, post-mortem interval, agonal state), or peripheral leukocytes (relevance of expression changes, painful blood draws) employed in previous studies. Alterations in the human microbiome (i.e., microbial communities) have also been shown to correlate with ASD. Thus, extracellular RNA quantification in saliva provides an attractive and minimally invasive technique for biomarker identification in children with ASD. This Phase II study will test the hypothesis that a pre-defined panel of human and non- human RNAs will accurately determine ASD status in a cohort of 1600 children ages 18 months to 6 years. Using prospective clinical trial methodology, with input from FDA, the project will provide data essential to the commercialization of Quadrant’s ASD diagnostic technology, further testing the algorithm with the inclusion of additional children and following children who are flagged with the currently utilized ASD to determine their ultimate diagnosis.

自闭症谱系障碍 (ASD) 是一系列神经发育特征，包括以下方面的缺陷：沟通和社交互动，以及限制性、重复性的兴趣和行为是一种自闭症谱系障碍（ASD）。公众对健康的关注日益增加，2014 年，大约每 45 名美国儿童中就有 1 人被诊断患有自闭症谱系障碍 (ASD)，这一比例增加了 10 倍过去 40 年来患病率不断上升，自闭症谱系障碍对社会和经济的影响都很大。据估计，仅在美国每年的负担就超过 2860 亿美元，而与 ASD 有直接联系。诊断尚未确定，研究已确定遗传、表观遗传、神经、激素和影响 ASD 患者预后的环境因素为了有效治疗 ASD 患者，及时发现对于利用这些预先存在的知识实施早期治疗方案至关重要。对于自闭症谱系障碍的因素，医生可以在患者还年轻时就开始治疗，即使孩子还没有开始表现出典型的 ASD 症状研究表明，早期治疗可以带来更好的功能结果和这些模型、药物和项目已被证明可以有效减轻自闭症谱系障碍的症状。控制自闭症谱系障碍的症状，并可能将一些患者完全从自闭症谱系障碍中剔除。不幸的是，目前的自闭症谱系障碍 (ASD) 诊断方法对于年幼的儿童来说并不是很准确；自闭症谱系障碍的诊断已有三年历史，其中大约一半是误报。因此，自闭症谱系障碍 (ASD) 的诊断生物标志物将为 Quadrant Biosciences 的患者护理提供宝贵的补充。正在开发一种通过测量大脑相关的核糖核酸和其他核糖核酸（微量、唾液中的 miRNA 通过外泌体和其他微泡进行胞外转运。建立了细胞改变附近细胞基因表达的表观遗传机制。测量可能源自中枢神经系统的遗传物质的象限只需通过这种方法最大限度地减少了与死后大脑分析相关的许多限制。组织（例如缺氧性脑损伤、RNA 降解、死后间隔、临终状态）或外周白细胞（表情变化的相关性、痛苦的抽血）在之前的人类研究中使用。微生物组（即微生物群落）也被证明与自闭症谱系障碍（ASD）相关。唾液定量为生物标志物鉴定提供了一种有吸引力的微创技术这项第二阶段的研究将测试一个假设，即预先定义的人类和非自闭症儿童。人类 RNA 将准确确定 1600 名 18 个月至 6 岁儿童的 ASD 状态。该项目将使用前瞻性临床试验方法，并根据 FDA 的意见，提供必要的数据。跨骏 ASD 诊断技术的商业化，进一步测试该算法，包括标记有当前使用的 ASD 的其他儿童和后续儿童以确定他们的最终诊断。