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

• 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
• 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

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的连续体，包括 交流和社会互动，以及限制性、重复性的兴趣和行为。ASD是一种 公共卫生问题日益受到关注，2014年约每45名美国儿童中就有1人被诊断为自闭症，是 在过去的40年里，患病率增加了。ASD对社会和经济的影响是巨大的 据估计，仅在美国每年就超过2,860亿美元。而与ASD的单一直接链接 诊断尚未确定，研究已确定遗传、表观遗传学、神经学、激素和 影响ASD患者预后的环境因素。为了有效地治疗ASD患者， 及时发现对于实施早期治疗方案至关重要。利用这些预先存在的知识 对于ASD的因素，医生可以在患者还小的时候就开始治疗，即使孩子还没有开始 表现出典型的ASD症状。研究表明，早期治疗会带来更好的功能结果， ASD症状的减轻。这些模式、药物和方案已被证明在 控制ASD的症状，并可能完全将一些患者从ASD谱系中移除。 不幸的是，目前对自闭症的诊断方法对幼儿不是很准确； 诊断ASD已经有三年的历史了，其中大约一半是假阳性。精确度的发展 因此，ASD的诊断生物标志物将是对患者护理的有价值的补充。象限生物科学 正在开发一种通过测量与大脑相关的和其他核糖核酸(微型、 唾液中的环状和细菌)。通过外切体和其他微囊进行miRNA的细胞外运输是一种 建立了细胞改变附近细胞基因表达的表观遗传机制。这已使 象限测量可能起源于中枢神经系统的遗传物质 收集唾液。这种方法最大限度地减少了与尸检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、死亡状态)或外周白细胞 (表情变化的相关性，痛苦的抽血)在以前的研究中使用。人类的变化 微生物群(即微生物群落)也被证明与ASD相关。因此，细胞外RNA 唾液中的定量提供了一种有吸引力的微创技术用于生物标志物鉴定 患有自闭症的儿童。这项第二阶段的研究将检验这样一种假设，即一个由人类和非人类组成的预定义小组 人类RNA将准确地确定1600名18个月到6岁的儿童的ASD状态。 使用前瞻性临床试验方法，在FDA的投入下，该项目将提供必要的数据 跨骏ASD诊断技术的商业化，进一步测试算法，包括 标记了当前使用的ASD的其他子项和后续子项以确定其 终极诊断。