GENE EXPRESSION EXON ARRAY BIOMARKERS TO DIAGNOSE SCHIZOPHRENIA

用于诊断精神分裂症的基因表达外显子阵列生物标志物

• 批准号: 7925104
• 负责人: Terry W Osborn
• 金额: $ 20万
• 依托单位: ABASTAR MDX, INC.
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-22 至 2012-06-21
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7925104
• 关键词: Address; Adult; Affect; Age; Alternative Splicing; Am 80; Amendment; American; Antipsychotic Agents; Arts; Award; Biological Markers; Biopsy; Bipolar Disorder; Blood; Blood specimen; Brain; Brain Diseases; Businesses; Caring; Categories; Cells; Chronic; Chronic Schizophrenia; Clinical; Clinical Research; Clinical assessments; Data; Detection; Development; Diagnosis; Diagnostic; Diagnostic tests; Disease; Drug abuse; Early treatment; Enrollment; Exons; FDA approved; Functional disorder; Future; Gender; Gene Expression; Gene Expression Profile; Genes; Genetic Transcription; Hospitalization; Hospitals; Hour; Individual; Intervention; Laboratories; Lead; Life; Logistic Regressions; Major Depressive Disorder; Measures; Medical; Mental disorders; Messenger RNA; Methods; Modeling; Molecular Profiling; Morbidity - disease rate; National Institute of Mental Health; Nature; Patients; Pharmaceutical Preparations; Physicians; Pilot Projects; Population; Process; Psychiatrist; Psychotic Disorders; RNA; Race; Recovery; Recurrence; Reporting; Research; Research Ethics Committees; Research Personnel; Rewards; Risk; Sampling; Schizophrenia; Severity of illness; Small Business Innovation Research Grant; Smoking; Symptoms; Testing; Time; Transcript; Validation; Visit; Whole Blood; abstracting; base; case control; catalyst; clinical research site; disability; effective therapy; falls; innovation; novel; product development; psychosocial; public health relevance; research clinical testing; sample collection; standard care; success; technological innovation; trait

DESCRIPTION (provided by applicant): AbaStar MDx RFA-OD-09-009, (R43), SBIR - Gene Expression Exon Array Biomarkers to Diagnose Schizophrenia Project Summary/Abstract This application RFA-OD-09-009, addresses Recovery Act Limited Competition: Small Business Catalyst Awards for Accelerating Innovative Research (R43). The proposal is titled: "Gene Expression Exon Array Biomarkers to Diagnose Schizophrenia". The National Institute of Mental Health is specifically seeking the development of biomarkers for psychiatric disorders. AbaStar MDx's long term aim is the development of a novel, innovative, commercially-viable means of genetically diagnosing and differentiating schizophrenia (SZ), bipolar disorder (BD) and Major Depressive Disorder (MDD) from normal/healthy individuals (NC) with mRNA gene expression signatures from a blood sample. Results will address significant clinical issues, provide faster and more accurate diagnoses, add to the understanding of shared and unique pathophysiologies of each disorder. Future success in this effort may alter medical treatment by providing more effective drugs, appropriate early interventions for mental disorders. The specific objective of this pilot study is to demonstrate predictive and, consistent surrogate biomarkers to diagnose SZ with dysregulated mRNA gene expression signature from blood samples at three different time points over three months. We have shown, in NC, 20% of the RNA transcripts measured on Affymetrix exon array were not significantly changed over nine consecutive blood draws time points over 54 hours. The remaining 80% were changed significantly. Well-known episodic nature of the disease might lead to highly variable results depending on when blood is collected in relation to the severity of the disease/symptoms. Variables, such as time of day of the sample collection, day to day variability might have an impact on the expression profile. Also another challenge addressed is that several researchers have confirmed dysregulated RNA genes in blood sample of SZ compared to NC. However, the SZ gene sets don't overlap from one study to the next and to date all samples were collected at one time point. The study would reveal variability of alternative splicing and confirm that we have the best set of biomarker genes for diagnostic product development. These criticisms from prior submissions have been addressed with this study with multiple blood draws from the same individuals over longer time periods to show consistency of the proposed RNA screen. If successful, this unique diagnostic could address a significant clinical problem and lead to the first blood based test for SZ. We will continue to standardize the experimental process, analyze RNA gene expression data, along with covariates and establish the most consistent possible RNA gene expression biomarker set. These chronic dysregulated gene sets for the disorder can be identified in this proposal (and validated in future studies) with these proposed association studies. This will be accomplished by: Enrolling well characterized chronic SZ patients, ages 18-45 with SZ (n=30) and NC (n=30) subjects at one clinical sites in an institutional review board (IRB) approved clinical study; Conducting clinical assessment then collect whole blood samples from SZ and NC subjects at 3- visits, over 3 months; Extracting high quality RNA from the whole blood samples and measuring RNA gene expression using on Affymetrix exon array; Analyzing statistically RNA gene expression data and alternative splicing, along with covariates throughout to control for the likely effects of cell specific expression, psychiatric symptom assessment scales, clinical lab tests, medications, smoking, drug abuse, ethnic, gender, from three time points; and At the Conclusion: Upon completion of Aims, we expect to have identified a set of mRNA transcripts in SZ that are consistently dysregulated compared to NC overtime and thus are best potential biomarkers to develop diagnostic products. The final commercialized products derived from this approach after validation of the biomarker signatures will be CLIA (Clinical Laboratory Improvement Amendments) lab tests ordered by psychiatrists, and ultimately FDA-approved diagnostic kits for use in hospitals and clinical reference labs. This technological innovation will revolutionize diagnoses and therapy for many types of mental disorders, saving lives, ameliorating morbidity, and rewarding patients with substantially better care. PUBLIC HEALTH RELEVANCE: AbaStar MDx RFA-OD-09-009, (R43), SBIR - Gene Expression Exon Array Biomarkers to Diagnose Schizophrenia Project Narrative The proposed effort is to demonstrate predictive and consistent surrogate biomarkers to diagnose SZ with dysregulated mRNA gene expression signature from blood samples at three different time points over three months. We expect to have identified a set of mRNA transcripts in SZ that are consistently dysregulated compared to NC over time. This will provide the best potential biomarkers to develop diagnostic products. This will establish new standards for treatment decisions for the 2.5 million American adults diagnosed with SZ. This technological innovation will revolutionize diagnoses and therapy for many types of mental disorders. It will also lead to saving lives, ameliorating morbidity, and rewarding patients with substantially better care. If successful, this transforming development will establish a revolutionary platform to address the myriad of other mental disorders affecting 57 million Americans for which no 'objective' clinical test yet exists.

DESCRIPTION (provided by applicant): AbaStar MDx RFA-OD-09-009, (R43), SBIR - Gene Expression Exon Array Biomarkers to Diagnose Schizophrenia Project Summary/Abstract This application RFA-OD-09-009, addresses Recovery Act Limited Competition: Small Business Catalyst Awards for Accelerating Innovative Research (R43).该提案的标题为：“基因表达外显子阵列生物标志物诊断精神分裂症”。美国国家心理健康研究所特别寻求开发精神疾病的生物标志物。 Abastar MDX的长期目标是开发一种新型，创新的，可获得的，可从正常/健康个体（NC）的遗传诊断和区分精神分裂症（SZ），双相情感障碍（BD）和主要抑郁症（MDD）的方法。结果将解决重大的临床问题，提供更快，更准确的诊断，增加对每种疾病共享和独特的病理生理的理解。在这项工作中的未来成功可能会通过提供更有效的药物，适当的精神障碍干预措施来改变医疗治疗。这项试验研究的具体目标是证明预测性和一致的替代生物标志物，以诊断三个月内三个不同时间点的血液样本中的mRNA基因表达信号失调的SZ。我们已经显示，在NC中，在Affymetrix外显子阵列上测量的RNA转录本中有20％在连续9个血液中没有显着改变54小时的时间点。其余的80％发生了显着更改。该疾病的众所周知的发作性质可能会导致高度可变的结果，具体取决于何时与疾病/症状的严重程度收集血液。变量，例如样本收集的日期，日常变异性可能会影响表达曲线。另外另一个挑战是，与NC相比，一些研究人员证实了SZ血液样本中的RNA基因失调。但是，SZ基因集并未从一项研究到另一项研究重叠，迄今为止，所有样品都是在一个时间点收集的。该研究将揭示替代剪接的可变性，并确认我们拥有最佳的生物标志物基因用于诊断产品开发。这项研究已经通过较长的时间段的多个血液抽血来解决了先前提交的批评，以显示拟议的RNA筛查的一致性。如果成功，这种独特的诊断可能会解决重大的临床问题，并导致对SZ的首次基于血液的测试。我们将继续标准化实验过程，分析RNA基因表达数据以及协变量，并建立最一致的RNA基因表达生物标志物集。这些慢性失调的基因集可以在本提案中（在未来的研究中验证）与这些拟议的关联研究进行鉴定。这将通过以下方式完成：在一个临床审查委员会（IRB）批准的临床研究中，在一个临床部位招募了18-45岁的慢性SZ患者，年龄在18-45岁的SZ（n = 30）和NC（n = 30）受试者； 然后进行临床评估，然后以3个月的时间从SZ和NC受试者收集全血样本； 从整个血液样本中提取高质量的RNA，并使用Affymetrix外显子阵列测量RNA基因表达； 分析统计上的RNA基因表达数据和替代剪接以及整个协变量，以控制细胞特异性表达，精神病症状评估量表，临床实验室测试，药物，吸烟，药物滥用，种族，性别，性别，从三个时间点开始并结论是：在完成目标后，我们预计与NC的加时性相比，SZ中的一组mRNA转录本始终被失调，因此是开发诊断产品的最佳潜在生物标志物。在验证生物标志物签名后，从这种方法得出的最终商业化产品将是由精神科医生下令的CLIA（临床实验室改进）实验室测试，最终是FDA批准的诊断套件，用于医院和临床参考实验室。这项技术创新将彻底改变许多类型的精神障碍的诊断和治疗，挽救生命，改善发病率，并奖励具有更好护理的患者。 公共卫生相关性：ABASTAR MDX RFA-OD-09-009，（R43），SBIR-基因表达外显子阵列生物标志物诊断精神分裂症项目叙事叙事是为了证明预测性和一致的替代生物标记物，以诊断出sz的MRNA基因表达在三个不同的时间点上诊断出三个不同的时间分三个不同的时间点。我们希望随着时间的流逝，与NC相比，SZ中的一组mRNA转录本始终持续失调。这将为开发诊断产品提供最佳潜在的生物标志物。这将为250万美国成年人诊断为SZ的美国成年人建立新的标准。这种技术创新将彻底改变许多类型的精神障碍的诊断和治疗。这也将导致挽救生命，改善发病率，并奖励具有更好护理的患者。如果成功的话，这种转变的发展将建立一个革命性的平台，以解决影响5700万美国人的其他精神障碍，而这些疾病尚无“客观”临床测试。