Development of an Autism Spectrum Disorder Screening Test based upon Metabolic Profiling of Fresh Blood Samples

基于新鲜血液样本代谢分析的自闭症谱系障碍筛查测试的开发

• 批准号: 9466602
• 负责人: Kevin D Champaigne
• 金额: $ 37.17万
• 依托单位: CIRCA BIOSCIENCE, LLC
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-13 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9466602
• 关键词: 10 year old; Age; Age-Months; Amino Acids; Attention deficit hyperactivity disorder; Autistic Disorder; B-Lymphocytes; Biochemical; Biological Assay; Biological Markers; Blinded; Blood; Blood Volume; Blood specimen; Cell Count; Cell Line; Cell Separation; Cells; Child; Clinical; Clinical Trials; Communication impairment; DSM-V; Data; Development; Developmental Delay Disorders; Diagnosis; Diagnostic; Diagnostic and Statistical Manual of Mental Disorders; Diagnostic tests; Dyes; Early Diagnosis; Early Intervention; Early treatment; Energy-Generating Resources; Evaluation; Exposure to; Gases; Goals; Immune; Individual; Interview; Investigation; Ions; Kinetics; Laboratories; Language; Lead; Legal patent; Leukocytes; Magnetism; Measures; Metabolic; Metabolic Pathway; Methods; Miniaturization; Neurodevelopmental Disorder; Oxidation-Reduction; Pathogenicity; Performance; Phase; Prevalence; Process; Production; Protocols documentation; Reciprocal Social Interaction; Risk; Sampling; Schedule; Sensitivity and Specificity; Series; Specificity; Standardization; Subgroup; System; Techniques; Technology; Temperature; Testing; Time; Toddler; Treatment Efficacy; Tryptophan; United States; age group; aged; autism spectrum disorder; base; behavior observation; behavioral outcome; cell immortalization; cell type; clinical Diagnosis; cohort; commercialization; cost; design; imaging modality; immortalized cell; immune activation; improved; individualized medicine; interest; intervention program; lymphoblastoid cell line; metabolic profile; novel; prototype; repetitive behavior; response; screening; social skills; testing services; treatment planning

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by significant deficits in reciprocal social interactions, impaired communication and restricted, repetitive behaviors, with a prevalence of 1 in 68 children in the US. Early intervention programs have been shown to be effective for improving IQ, language, and social skills for toddlers as young as 18 months of age. Diagnosis of ASD is currently based solely on clinical and parental observations, as a laboratory-based diagnostic test for ASD based on robust biomarkers does not exist currently. Our team previously demonstrated that lymphoblastoid cell lines (LCLs) from individuals with ASD generate reduced metabolic activity when the amino acid tryptophan is the only available energy source, relative to typically developing (TD) controls. In a recent evaluation of 50 ASD and 50 TD cell lines from individuals aged 1 to 10, a classifier utilizing a Bootstrap aggregation approach based upon tryptophan and an expanded series of ions was able to properly classify individual cell lines with both a sensitivity and specificity of 92% relative to the clinical diagnosis. The classifier showed better performance in the younger age groups, particularly in individuals aged 1 to 3, which is also the ideal target range for a screening test for ASD. The development of a laboratory biomarker test based on these patented methods will potentially serve as a second tier objective test following initial behavioral observations have identified a child at risk of developing ASD, thereby providing for confirmation of the diagnosis and earlier treatment. Potentially, such a test will also (1) lead to a better understanding of the pathogenic mechanisms underlying this condition, (2) assist in the identification of biochemical signatures delineating ASD sub-groups, and (3) highlight novel targets for improved and individualized treatment approaches. Widespread use of the existing test methods, however, is currently limited either by the cost and time associated with generating immortalized cell lines for each sample or by the size of the fresh blood sample that can be acquired from children, which is necessary to obtain sufficient numbers of live cells for the metabolic profiling assay. Therefore, the objective of the proposed effort is to develop methods and technologies to perform metabolic profiling on immune cells from small volumes of fresh blood to enable a viable screening test for ASD. Efforts will first be focused on improving the sensitivity of the current live-cell metabolic profiling techniques. Miniaturization of the assay platform will then be implemented to reduce the number of cells needed for each test condition, thereby limiting the necessary blood sample volume. Blood samples from a minimum of 100 subjects diagnosed with ASD and 100 TD controls will undergo metabolic profiling in a blinded fashion according to the methods and protocols developed. The performance of multiple classifiers will then be evaluated to determine the ability of the techniques to identify individuals diagnosed with ASD. The successful completion of this effort will lead directly to the Phase 2 investigation, which will involve testing an expanded cohort, including other neurodevelopmental disorders, and finalizing the design of a commercially viable testing service, platform, or kit. Commercialization of the technology proposed will ultimately provide for a screening test to identify toddlers at increased risk for ASD, thereby providing for earlier diagnosis and improved behavioral outcomes.

自闭症谱系障碍（ASD）是一种神经发育障碍，其特征是相互缺陷 社交互动，沟通受损和受限制的重复行为，有68名儿童的患病率 美国。早期干预计划已被证明可有效提高智商，语言和社交技能 幼儿年仅18个月大。 ASD的诊断目前仅基于临床和父母观察， 作为基于强大的生物标志物的基于实验室的ASD诊断测试，目前尚不存在。我们的团队以前 证明来自ASD个体的淋巴母细胞系（LCLS）会产生降低的代谢活性 相对于通常发育（TD）控件，氨基酸色氨酸是唯一可用的能源。在最近的一个 评估1至10岁个体的50个ASD和50 TD细胞系，使用引导程序聚集的分类器 基于色氨酸和扩展的离子系列的方法能够与 相对于临床诊断，敏感性和特异性均为92％。分类器在 年龄较小，特别是在1至3岁的个体中，这也是筛选测试的理想目标范围 ASD。基于这些专利方法的实验室生物标志物测试的开发将有可能作为第二次 初始行为观察以后的层次目标测试已经确定了有患ASD风险的孩子，从而 提供确认诊断和早期治疗。潜在地，这样的测试也将（1）导致更好 了解这种情况下的致病机制，（2）有助于鉴定生化 签名描述ASD子组，（3）突出显示改进和个性化处理的新目标 方法。但是，目前广泛使用现有测试方法的成本和时间受到限制 与每个样品或通过新鲜血液样本的大小产生永生的细胞系有关 从儿童中获得，这是获得足够数量的活细胞进行代谢分析测定所必需的。 因此，拟议的努力的目的是开发方法和技术以在 来自少量新鲜血液的免疫细胞可为ASD进行可行的筛查测试。努力将首先集中 在提高当前活细胞代谢分析技术的敏感性方面。测定平台的小型化 然后将实施以减少每个测试条件所需的单元格数，从而限制必要的 血液样本体积。至少有100名诊断为ASD和100 TD控制的受试者的血液样本将 根据开发的方法和协议以盲目的方式进行代谢分析。性能 然后将评估多个分类器，以确定这些技术识别诊断为诊断的人的能力 ASD。这项工作的成功完成将直接导致第二阶段调查，这将涉及测试 扩展的队列，包括其他神经发育障碍，并最终确定商业可行的测试的设计 服务，平台或套件。提议的技术的商业化最终将提供筛选测试 确定ASD风险增加的幼儿，从而为早期诊断和行为结果改善提供了。