Development and Commercialization of Ocular Diagnostic Tests Based on Vitreous Pr

描述（由申请人提供）：年龄相关性黄斑变性（AMD）是发达国家60岁以上人群视力丧失和失明的主要原因。这种疾病的进展导致丧失与生活质量高度相关的活动能力。这种疾病的发病过程尚不清楚。治疗只能解决部分潜在机制的疾病，没有治愈。目前的治疗标准是反复玻璃体内抗血管内皮生长因子（anti-VEGF）药物治疗。然而，只有34%-40%的患者获得了临床上显著的视力，并在一到两年的时间里保持了这种视力。目前，只有在数月无效治疗后才能确定无反应。我们的目标是验证一组生物标志物，以预测抗vegf单药治疗的临床无反应，以便医生能够快速识别将从替代治疗中受益的患者，而不是等待数月才能在实施其他治疗策略之前临床证明治疗失败。我们发现在人眼玻璃体液中存在细胞受体及其活化磷酸化形式，并且在抗vegf治疗应答者和无应答者之间存在显著的蛋白质水平差异。Ocular Proteomics, LLC （OPL）的方法将基于反相蛋白微阵列（RPPM）技术的使用，以准确区分高危患者的不同疾病状态。OPL是一个使用RPPM技术研究退行性眼部疾病生物标志物的小组的前沿。该结果将为该项目研究玻璃体蛋白质组对视网膜疾病（包括湿性AMD）的预测潜力铺平道路。1)湿性AMD患者的基线蛋白质组不同于健康正常人或其他类型眼病患者。2)湿性AMD抗vegf治疗无应答者与湿性AMD应答者的玻璃体蛋白组基线差异显著。3)应答者和无应答者基线蛋白质组的差异可能在于参与VEGF、血管生成和/或炎症途径的蛋白质。该提案的具体目标是：（目标1）使用临床反应模型形成玻璃体样本队列进行生物标志物分析；（目标2）使用抗体微阵列分析候选玻璃体生物标志物；（目标3）验证和量化生物标志物。

DESCRIPTION (provided by applicant): Age-related macular degeneration (AMD) is the leading cause of vision loss and blindness in people over age 60 in the developed world. Progression of this disease results in the loss of the ability to perform activities highly correlated with quality of life. The disease process is not well understood. Treatments address only portions of the underlying mechanisms of the disease and there is no cure. The current standard of care is repeated intravitreal anti-vascular endothelial growth factor (anti-VEGF) pharmacologic treatment. However, only 34%-40% of patients gain clinically significant vision and maintain that gain over the course of one to two years. Currently non-responders are identified only after months of ineffective treatment. Our objective is to validate a panel of biomarkers that predict clinical non-responders to anti-VEGF monotherapy so that physicians can quickly identify patients who would benefit from alternative therapy rather than waiting for months to clinically demonstrate treatment failure before implementing these other therapeutic strategies. We have discovered the presence of cell receptors and their activated phosphorylated forms in the vitreous fluid of human eyes and that there are significant protein level differences between anti-VEGF treatment responders and non-responders. Ocular Proteomics, LLC (OPL)'s approach will be based on the use of reverse-phase protein microarray (RPPM) technology to accurately discriminate different disease states in at-risk patients. OPL is at the forefront of a small group that uses RPPM technology to investigate biomarkers for degenerative ocular diseases. Results will lead the way for this project to study the predictive potential of the vitreous proteome for retinal diseases, including wet AMD. Hypotheses 1) The baseline proteome of wet AMD patients is distinctive from that of healthy normals or patients with other types of eye diseases. 2) The baseline vitreous proteome of wet AMD non-responders to anti-VEGF therapy differs significantly from that of wet AMD responders. 3) Differences in the baseline proteome of responders and non-responders are likely to lie in proteins involved in the VEGF, angiogenesis, and/or inflammatory pathways. The Specific Aims of the proposal are: (Aim 1) use model of clinical response to form cohorts of vitreous samples for biomarker analysis, (Aim 2) profile candidate vitreous biomarkers using antibody microarrays, and (Aim 3) validate and quantify the biomarkers. PUBLIC HEALTH RELEVANCE: The proposed research will improve public health by improving the vision of patients with wet age-related macular degeneration at reduced costs. It will do this by producing a product that will allow retina physicians to perform a test that will determine how a patient will respond to a given treatment before starting the patient on this treatment. This will allow the doctor to choose the right treatment for the right patient at the right time, providing truly personalized medicine.