Using a novel model of antidepressant efficacy to discover new compounds and personalized treatments.

使用抗抑郁功效的新模型来发现新化合物和个性化治疗。

• 批准号: 9468094
• 负责人: MARK M. RASENICK
• 金额: $ 39.95万
• 依托单位: PAX NEUROSCIENCE, INC.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-20 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9468094
• 关键词: Address; Adenoviruses; Adenylate Cyclase; American; Antidepressive Agents; Area; Behavior Therapy; Binding; Biological Assay; Biological Markers; Blood Tests; Cell Line; Cells; Cellular Membrane; Clinical; Clinical Research; Clinical Trials; Comorbidity; Computer software; Coupling; Data; Depressed mood; Development; Diabetes Mellitus; Diagnosis; Diagnostic; Diagnostic tests; Disease remission; Enrollment; Escitalopram; Failure; Fibroblasts; Fluorescence Recovery After Photobleaching; Funding; G-substrate; GTP-Binding Protein alpha Subunits, Gs; GTP-Binding Proteins; Glioma; Goals; Heart Diseases; Human; Image Analysis; Impairment; Knowledge; Legal patent; Libraries; Major Depressive Disorder; Medical; Medical Economics; Membrane Microdomains; Mental Depression; Mental disorders; Modeling; Molecular Target; Mood Disorders; Movement; National Institute of Mental Health; Neuroblastoma; Neurons; Neurosciences; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Physicians; Population; Recovery; Recruitment Activity; Retreatment; Running; Sampling; Schizophrenia; Services; Small Business Innovation Research Grant; Source; Study models; Technology; Testing; Therapeutic; Time; Transgenes; Treatment Efficacy; United States National Institutes of Health; Work; World Health Organization; accurate diagnosis; anxiety symptoms; base; biosignature; clinical diagnostics; commercialization; cost; depressive symptoms; diagnostic biomarker; disability; experimental study; glioma cell line; improved outcome; individualized medicine; innovation; mutant; nerve stem cell; novel; novel therapeutics; patient population; personalized medicine; personalized therapeutic; preclinical study; predicting response; primary care setting; protein biomarkers; response; scaffold; screening; serotonin transporter; small molecule; social; suicidal risk; treatment response

The World Health Organization estimates that by 2020, major depressive disorder (MDD) will be the most common cause of disability, worldwide. Although approximately 1 in 6 Americans will suffer from MDD during their lifetime, many patients with MDD go undiagnosed in primary care settings, and 20% are incorrectly diagnosed with MDD. Given the substantial medical, economic and social costs involved with MDD, there is tremendous need for a simple objective biomarker test to aid clinicians in accurately identifying MDD. No test currently exists that can accurately diagnose MDD and distinguish it from other psychiatric conditions. Further, clinical response to antidepressant therapy requires as much as two months. There is enormous need for a test that can predict response within a few days of the inception of treatment. The potential market for an accurate diagnostic test for MDD is estimated at $5-8B annually. Payers of medical services would cover the cost of such a diagnostic test because accurately identifying and treating MDD would reduce the high medical costs arising from medical service delivery to patients with untreated depression, as well as improving outcomes for patients with comorbid medical conditions such as diabetes or heart disease. Another market for an MDD diagnostic test is pharmaceutical companies. These companies have uniformly retreated from discovery efforts in mood disorders, in part due to large- scale failure of numerous clinical trials. Part of the reason for these failures is the enrollment of inappropriate patients. An objective test of MDD could address this concern by providing certainty about the appropriateness of recruited subjects. The Pax Neuroscience diagnostic biomarker Gαs Sequestration Assay (GSA) indicates that MDD patients have a significantly greater proportion of Gαs captured in lipid rafts compared to non-depressed controls and can accurately identify patients suffering from MDD. Pax used the same principles that underpin the GSA to develop a C6 glioma (Gαs -GFP) FRAP assay which can reliably predict antidepressant efficacy. The proposed studies will convert that assay into high content screening (HCS) format, enabling an HCS campaign to find novel small molecules that target MDD. In addition we will develop a secondary screen using Neural Stem Cells, i n d u c e d from f i b r o b l a s t s o f d e p r e s s e d subjects with known responses to antidepressants (SSRIs), to confirm the efficacy of the screen. This secondary screen can be modified to evaluate treatment efficacy in MDD patients. This is an exciting proposal that offers an underlying technology that can both find new drugs and develop personalized therapy for depression.

世界卫生组织估计，到 2020 年，重度抑郁症（MDD）将成为全球最严重的抑郁症。 全球范围内最常见的残疾原因。尽管大约六分之一的美国人患有重度抑郁症 许多 MDD 患者一生中都没有在初级保健机构中得到诊断，其中 20% 被错误诊断为MDD。鉴于 MDD 所涉及的巨大医疗、经济和社会成本， 非常需要一种简单客观的生物标志物测试来帮助临床医生准确识别 MDD。 目前还没有任何测试可以准确诊断重度抑郁症并将其与其他精神疾病区分开来。 此外，抗抑郁治疗的临床反应需要长达两个月的时间。有巨大的需求 一项可以预测治疗开始后几天内反应的测试。潜在市场 MDD 的准确诊断测试每年估计花费 5-8B 美元。医疗服务的支付者将涵盖 这种诊断测试的成本，因为准确识别和治疗 MDD 会降低高风险 向未经治疗的抑郁症患者提供医疗服务所产生的医疗费用，以及改善 患有糖尿病或心脏病等合并症的患者的结果。 MDD 诊断测试的另一个市场是制药公司。这些公司有 一致从情绪障碍的发现努力中撤退，部分原因是许多研究的大规模失败 临床试验。这些失败的部分原因是招募了不合适的患者。客观测试 MDD 可以通过确定招募受试者的适当性来解决这一问题。 Pax Neuroscience 诊断生物标志物 Gαs 隔离测定 (GSA) 表明 MDD 与非抑郁症患者相比，患者脂筏中捕获的 Gα 比例明显更高 控制并能够准确识别患有 MDD 的患者。帕克斯使用了与支撑相同的原则 GSA 开发了一种 C6 神经胶质瘤 (Gαs -GFP) FRAP 检测方法，可以可靠地预测抗抑郁功效。 拟议的研究将将该测定转换为高内涵筛选 (HCS) 格式，从而实现 HCS 寻找针对 MDD 的新型小分子的活动。此外，我们将使用以下方式开发辅助屏幕 神经干细胞，由具有已知反应的抑郁受试者的成纤维细胞诱导而来 抗抑郁药（SSRIs），以确认筛查的功效。该辅助屏幕可以修改为 评估 MDD 患者的治疗效果。这是一个令人兴奋的提案，提供了基础技术 既可以寻找新药，又可以开发抑郁症的个性化疗法。