Evaluation of New Anti-inflammatory Treatments for Age-Related Macular Degeneration

项目摘要 视网膜相关性黄斑变性（AMD）是美国第三大致盲原因， 全世界失明的原因。最初，干性AMD是由过量活性氧引起的炎症引起的 物种（ROS），并没有治愈。当它进展到湿性AMD时，疾病的特征是异常的 血管内皮生长因子（VEGF）过度表达引起的渗漏血管的生长， 永久性损伤视网膜并导致严重的视力丧失。抗VEGF治疗是目前的标准 治疗湿性AMD。然而，频繁玻璃体内注射的需要与高的玻璃体内注射相关。 治疗费用、患者负担和包括疼痛在内的并发症风险。这也没有解决 疾病早期阶段的炎症成分。临床上需要减少注射频率 并治疗引起疾病的潜在炎症。该项目的总体目标是开发和 验证可注射的、可生物降解的、刺激响应的纳米颗粒递送系统， 一种治疗炎症的新疗法已持续数月。在目标1中，研究性治疗药物将 合成和表征了刺激响应性聚多巴胺纳米颗粒，释放更多的治疗， 活性氧物质（ROS）的存在将被合成并负载新的治疗剂。 将评价治疗剂和纳米颗粒在人视网膜色素上皮细胞中的体外细胞摄取 流式细胞仪检测细胞中的DNA含量。将评价治疗剂和纳米颗粒的短期生物相容性 在小鼠模型中体内培养2周。在目标2中，体内生物相容性和拟定治疗的有效性 将在2个月内在干性AMD的碘酸钠小鼠模型中进行评价。结构和功能 眼睛的评估将包括眼内压、眼底成像、光谱域光学相干性 断层扫描、组织学和免疫组织化学。将评估生物相容性和生物降解性 同时。2个月后，将通过ELISA验证眼组织中的治疗浓度。ELISA将 也可用于评估疾病模型中HO-1的视网膜表达水平，以研究 建议的治疗作用。这些目标将评估ROS响应的药物递送系统，以维持 在眼睛中释放抗炎治疗剂。这有可能治疗潜在的疾病途径 减少玻璃体内注射，改善AMD患者的生活质量， 其他眼部或炎症性疾病。

PROJECT SUMMARY Age-related macular degeneration (AMD) is the third leading cause of blindness in the US and one of the leading causes of blindness worldwide. Initially, dry AMD results from inflammation caused by excess reactive oxygen species (ROS), and has no cure. When it progresses to wet AMD, the disease is characterized by abnormal growth of leaky blood vessels caused by excess expression of vascular endothelial growth factor (VEGF), which permanently damages the retina and causes severe vision loss. Anti-VEGF therapeutics are the current standard treatment for wet AMD. However, the requirement of frequent intravitreal injections is associated with high treatment costs, patient burden, and risk of complications including pain. This also does not address the inflammatory component of early stages of the disease. There is a clinical need to reduce injection frequency and treat underlying inflammation causing the disease. The overall objective of this project is to develop and validate an injectable, biodegradable, stimuli-responsive nanoparticle delivery system that can sustain release of a new therapeutic to treat inflammation for several months. In Aim 1, an investigational therapeutic will be synthesized and characterized. Stimuli-responsive polydopamine nanoparticles that release more therapeutic in the presence of reactive oxygen species (ROS) will be synthesized and loaded with the new therapeutic. Therapeutic and nanoparticles will be evaluated for in vitro cellular uptake in human retinal pigment epithelial cells using flow cytometry. Short-term biocompatibility of both the therapeutic and nanoparticles will be evaluated in vivo in a mouse model over 2 weeks. In Aim 2, in vivo biocompatibility and efficacy of the proposed treatments will be evaluated in the sodium iodate mouse model of dry AMD over 2 months. Structural and functional assessments of the eye will include intraocular pressure, fundus imaging, spectral domain optical coherence tomography, histology, and immunohistochemistry. Biocompatibility and biodegradation will be assessed concurrently. Therapeutic concentrations in ocular tissues will be validated by ELISA after 2 months. ELISA will also be used to evaluate retinal expression levels of HO-1 in the disease model to investigate the mechanism of action of the proposed therapeutic. These aims will evaluate a ROS-responsive drug delivery system to sustain release of an anti-inflammatory therapeutic in the eye. This has potential to treat underlying disease pathways associated with AMD and reduce intravitreal injections, improving the quality of life for patients with AMD and other ocular or inflammatory diseases.