GENE EXPRESSION EXON ARRAY BIOMARKERS TO DIAGNOSE SCHIZOPHRENIA

描述(由申请人提供)：ABAStar MDX RFA-OD-09-009，(R43)，SBIR-基因表达外显子阵列生物标记物用于诊断精神分裂症项目摘要/摘要本申请RFA-OD-09-009，解决复苏法案有限竞争：小型企业催化剂加速创新研究奖(R43)。该提案的标题是：“用于诊断精神分裂症的基因表达外显子阵列生物标记物”。国家精神卫生研究所正在专门寻求开发用于精神障碍的生物标记物。AbaStar MDX的长期目标是开发一种新颖的、创新的、商业上可行的方法，从血液样本的mRNA基因表达签名对精神分裂症(SZ)、躁郁症(BD)和严重抑郁障碍(MDD)进行基因诊断，并将其与正常/健康个体(NC)区分开来。结果将解决重大的临床问题，提供更快和更准确的诊断，增加对每种疾病共同和独特的病理生理学的了解。未来这一努力的成功可能会通过为精神障碍提供更有效的药物和适当的早期干预来改变医疗治疗。这项初步研究的具体目标是在三个月内的三个不同时间点从血液样本中展示预测和一致的替代生物标记物，以诊断具有异常mRNA基因表达特征的SZ。我们已经表明，在NC中，在Affymetrix外显子阵列上测量的20%的RNA转录本在54小时内连续9个采血时间点没有显著变化。其余80%的人发生了显著变化。众所周知，这种疾病的间歇性可能导致高度不同的结果，这取决于采集血液的时间与疾病/症状的严重程度。变量，如样本采集的时间，每天的可变性可能会对表达谱产生影响。另一个解决的挑战是，几位研究人员已经证实，与NC相比，SZ的血液样本中存在调控异常的RNA基因。然而，从一项研究到下一项研究，SZ基因组并不重叠，到目前为止，所有样本都是在一个时间点收集的。这项研究将揭示选择性剪接的可变性，并确认我们拥有用于诊断产品开发的最佳生物标记基因集。之前提交的这些批评已经在这项研究中得到了解决，该研究在更长的时间段内从同一个人身上多次抽血，以显示拟议的RNA筛选的一致性。如果成功，这种独特的诊断可能会解决一个重大的临床问题，并导致第一个基于血液的SZ测试。我们将继续规范实验过程，分析RNA基因表达数据以及协变量，并建立尽可能一致的RNA基因表达生物标志物集。这些慢性失调的基因集可以在这项建议中被识别(并在未来的研究中得到验证)与这些拟议的关联研究。这将通过以下方式完成：在机构审查委员会(IRB)批准的临床研究中，在一个临床地点招募特征良好的慢性SZ患者，年龄18-45岁的SZ(n=30)和NC(n=30)；进行临床评估，然后在3次访问时收集SZ和NC的全血样本，超过3个月；从全血样本中提取高质量的RNA，并在Affymetrix外显子阵列上测量RNA基因的表达；统计分析RNA基因表达数据和选择性剪接，以及从头到尾的协变量，从三个时间点控制细胞特异性表达、精神症状评估量表、临床实验室测试、药物、吸烟、药物滥用、种族、性别的可能影响；并得出结论：在完成AIMS后，我们预计已经在SZ识别出一组与NC加班相比持续失调的mRNA转录本，因此是开发诊断产品的最佳潜在生物标记物。在验证生物标记物签名后，这种方法产生的最终商业化产品将是精神病学家订购的CLIA(临床实验室改进修正案)实验室测试，并最终获得FDA批准的诊断试剂盒，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精神障碍的诊断和治疗，挽救生命，改善发病率，并为患者提供更好的护理。 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记物诊断精神分裂症项目描述拟议的努力是为了展示可预测和一致的替代生物标记物，以诊断三个月内三个不同时间点的血液样本中存在基因表达异常的SZ。我们期望在SZ中鉴定出一组与NC相比一直处于失调状态的mRNA转录本。这将为开发诊断产品提供最有潜力的生物标志物。这将为250万被诊断为SZ的美国成年人的治疗决定建立新的标准。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。它还将拯救生命，改善发病率，并为患者提供更好的护理。如果成功，这一变革性的发展将建立一个革命性的平台，以解决影响5700万美国人的无数其他精神疾病，目前还没有针对这些疾病的“客观”临床测试。

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.