Validation of a salivary miRNA diagnostic test for autism spectrum disorder

自闭症谱系障碍（ASD）是一个连续的神经发育特征，包括缺陷， 沟通和社会互动，以及限制性的，重复性的兴趣和行为。ASD是一个 越来越多的公共卫生问题，2014年约有1/45的美国儿童被诊断患有ASD，是2014年的10倍。 在过去的40年里，流行率有所上升。ASD对社会和经济的影响很大， 据估计，仅在美国每年就有超过2860亿美元的负担。虽然与ASD的单一直接链接 诊断尚未确定，研究已经确定了遗传，表观遗传，神经，激素， 影响ASD患者预后的环境因素。为了有效治疗ASD患者， 及时发现对实施早期治疗方案至关重要。利用这些已有的知识 ASD的因素，医生可以开始治疗，而病人还年轻，即使孩子还没有开始 表现出典型的ASD症状研究表明，早期治疗可以获得更好的功能结果， 减少ASD的症状。这些模型，药物和计划已被证明是有效的， 控制ASD的症状，并可能完全将一些患者从ASD谱中移除。 不幸的是，目前ASD的诊断方法对幼儿不是很准确; 诊断ASD是三年前的事了，其中大约一半是假阳性。发展精准 因此，ASD的诊断生物标志物将代表对患者护理的有价值的补充。跨骏生物科学 正在开发一种通过测量大脑相关和其他核糖核酸（微， 圆形的和细菌性的）。miRNA通过外泌体和其他微囊泡的细胞外转运是一个重要的机制。 建立了细胞改变附近细胞基因表达的表观遗传机制。这使 象限测量遗传物质，可能已经从中枢神经系统起源， 收集唾液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、濒死状态）或外周白细胞 （表达变化的相关性，痛苦的抽血）。人类基因的改变 微生物组（即，微生物群落）也已显示与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和微创的生物标志物鉴定技术， ASD儿童这项II期研究将测试一个预先定义的人类和非人类群体的假设， 人类RNA将准确地确定1600名年龄为18个月至6岁的儿童的ASD状态。 采用前瞻性临床试验方法，在FDA的输入下，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 其他儿童和以下儿童被标记有当前使用的ASD，以确定他们的 最终诊断

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.