Development and Commercialization of Predictive Biomarker Panel and In-Office Kit for the Management of Diabetic Macular Edema

摘要 糖尿病黄斑水肿(DME)是糖尿病视网膜病变(DR)中威胁视力的阶段，可导致合法的 失明。驱动DME进展的生化机制尚未被很好地了解和治疗 仅针对疾病病理的一部分进行说明。可供选择的治疗方法从注射抗-HBs到不同的治疗方法差别很大。 血管内皮生长因子用于激光治疗的注射类固醇，给美国带来了沉重的成本负担，超过5亿美元 每年。目前，可用的治疗方案存在两个大问题：每种方案的疗效 治疗方法因人而异，持续的反应是不可预测的。给定 诊断的显著增加和巨大的公共成本负担，有必要开发新的 功能生物标记物诊断，帮助医生为每个患者选择最有效的治疗方法。 我们正在开发一种DME的配套诊断分析，可以在临床环境中使用，以 医生要预测抗血管内皮生长因子治疗的结果，这是DME的一线治疗方法。这项化验将使 为每个DME患者进行个性化治疗，在开始DME治疗之前确定适当的治疗方法， 何时切换治疗，何时可以安全地停止治疗(目前不可能)。 此外，由于该分析是由专门针对DME的生物标志物组成的，因此它可以用于制药 发现、开发和测试用于二甲基醚的新药或再利用药物的公司。 我们假设，玻璃体蛋白质组中相关通路的蛋白质组学分析以及与 接受抗血管内皮生长因子治疗的DME患者的临床症状将使我们能够制定一种预测性 DME中抗血管内皮生长因子反应的生物标志物小组。 我们将使用反相蛋白质芯片检测从DME收集的玻璃体样本中的蛋白质 随着时间的推移接受抗血管内皮生长因子治疗的患者。检测的目标包括与以下物质相关的蛋白质 血管生成/增殖、炎症/免疫反应、缺血/缺氧和细胞凋亡/细胞存活。 将进行统计分析，以检查玻璃体蛋白水平是否与 每月抗血管内皮生长因子治疗对视网膜厚度和视力的影响。以下是具体目标 旨在测试我们的假设并确定预测治疗反应的生物标志物小组：(1)确定 抗血管内皮生长因子对视网膜厚度和视力影响的生化途径 治疗，以及(2)确定一组预测视网膜厚度和视力变化的生物标志物 抗血管内皮生长因子治疗的敏感度 该项目的成功完成将导致开发一种预测生物标志物小组的形式 一个配套的诊断试剂盒，帮助临床医生为每个DME患者确定最有效的治疗方法。 此外，我们的发现将使我们能够与制药公司合作开发新的药物靶点。

Abstract Diabetic Macular Edema (DME) is a vision-threatening stage in Diabetic Retinopathy (DR) that can result in legal blindness. The biochemical mechanisms that drive DME progression are not well understood and treatments address only portions of the disease pathology. The available treatment options vary widely from injectable anti- VEGF to injectable steroids to laser treatments, and carry a heavy cost burden to the US, at over $500 million per year. Currently, there are two large problems with the available treatment options: the efficacy of each treatment is highly variable from patient to patient, and sustained responses are unpredictable. Given the significant increase in diagnoses and the enormous public cost burden, there is a need to develop novel functional biomarker diagnostics which assist physicians in choosing the most effective therapy for each patient. We are developing a companion diagnostic assay for DME which can be used in a clinic setting to allow physicians to predict outcome to anti-VEGF treatment, the first-line of therapy for DME. This assay will enable personalized therapy for each DME patient, by determining appropriate therapy before DME treatment is started, when to switch treatments, and when treatment can be safely stopped (which is currently not possible). Furthermore, as the assay is composed of biomarkers specifically for DME, it can be utilized by pharmaceutical companies for discovery, development, and testing of novel or repurposed drugs for DME. We hypothesize that proteomic analysis of relevant pathways in the vitreous proteome and correlation with clinical symptoms of DME patients receiving anti-VEGF treatment will enable us to develop a predictive biomarker panel for anti-VEGF response in DME. We will use Reverse Phase Protein Microarray assay to detect proteins in vitreous samples collected from DME patients receiving anti-VEGF treatment over time. Targets to be tested include proteins associated with angiogenesis/proliferation, inflammation/ immune response, ischemia/hypoxia and apoptosis/cell survival. Statistical analysis will be performed to examine whether vitreous protein levels are correlated to changes in retinal thickness and visual acuity in response to monthly anti-VEGF treatment. The following specific aims are designed to test our hypothesis and to identify a biomarker panel that predicts treatment response: (1) Identify biochemical pathways involved in changes in retinal thickness and visual acuity in response to anti-VEGF treatment, and (2) Identify a panel of biomarkers that is predictive of changes in retinal thickness and visual acuity in response to anti-VEGF treatment Successful completion of this project will lead to the development of a predictive biomarker panel in the form of a companion diagnostic kit that assists clinicians in determining the most effective therapy for each DME patient. Furthermore, our findings will allow us to collaborate with pharma companies in development of new drug targets.