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

项目总结 老年性黄斑变性(AMD)是美国第三大致盲原因，也是导致失明的主要原因之一 世界范围内的失明原因。最初，干性AMD是由过多的活性氧引起的炎症引起的。 物种(ROS)，并且没有治愈方法。当它发展到湿性AMD时，该病的特征是异常 血管内皮生长因子(VEGF)过度表达引起的渗漏血管的生长 永久性损害视网膜并导致严重的视力丧失。抗血管内皮生长因子治疗是目前的标准 湿性AMD的治疗。然而，频繁的玻璃体内注射的要求与高 治疗成本、患者负担以及包括疼痛在内的并发症风险。这也没有解决 疾病早期阶段的炎性成分。临床上有必要减少注射频率 并治疗导致这种疾病的潜在炎症。这个项目的总体目标是开发和 验证一种可注射、可生物降解、刺激响应型、可持续释放的纳米粒递送系统 一种治疗炎症的新疗法已经持续了几个月。在目标1中，调查性治疗将是 合成并表征了该化合物。刺激响应性多巴胺纳米粒在体内释放更多治疗性 活性氧物种(ROS)的存在将被合成并装载到新的治疗方法中。 治疗药物和纳米颗粒将评估人视网膜色素上皮细胞的体外摄取 用流式细胞仪检测细胞数量。治疗药物和纳米粒的短期生物相容性将进行评估。 在小鼠体内模型中超过2周。在目标2中，拟议治疗的体内生物相容性和疗效 将在2个月以上的干性AMD小鼠模型中进行评估。结构和功能 对眼睛的评估将包括眼压、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。将评估生物兼容性和生物降解性 同时。眼组织的治疗浓度将在2个月后用ELISA法验证。酶联免疫吸附试验 也可用来评估视网膜HO-1在疾病模型中的表达水平，以探讨其作用机制 建议的治疗师的行动。这些目标将评估ROS响应性药物输送系统以维持 在眼睛里释放一种抗炎治疗药物。这有可能治疗潜在的疾病途径。 与AMD相关并减少玻璃体内注射，改善AMD患者和 其他眼部疾病或炎症性疾病。

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.