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

年龄相关性黄斑变性的新型抗炎治疗方法的评价

• 批准号: 10642988
• 负责人: Katelyn E Swindle-Reilly
• 金额: $ 15.24万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-30 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10642988
• 关键词: Affect; Age related macular degeneration; Albumins; Animal Model; Anti-Inflammatory Agents; Apoptosis; Binding; Biodegradation; Blindness; Blood Vessels; Cells; Clinical; Data; Disease; Disease Pathway; Disease Progression; Disease model; Dose; Drug Delivery Systems; Enzyme-Linked Immunosorbent Assay; Evaluation; Eye; Eye diseases; Flow Cytometry; Frequencies; Future; Goals; Growth; Health; Healthcare Systems; Heme; High Pressure Liquid Chromatography; Histology; Human; Immunohistochemistry; In Vitro; Inflammation; Inflammatory; Injectable; Injections; Longevity; Measures; Microglia; Modeling; Mus; Neurodegenerative Disorders; Nonexudative age-related macular degeneration; Optical Coherence Tomography; Outcome; Oxidative Stress; Pain; Patients; Persons; Pharmaceutical Preparations; Physiologic Intraocular Pressure; Physiology; Pre-Clinical Model; Quality of life; Reactive Oxygen Species; Research; Research Personnel; Retina; Risk; Safety; Serum Albumin; Stains; Stimulus; Structure of retinal pigment epithelium; System; Testing; Therapeutic; Tissues; Translations; Treatment Cost; Treatment Efficacy; Validation; Vascular Endothelial Growth Factors; Vision; Work; adverse event risk; age related; barrier to care; biomaterial compatibility; clinical examination; combinatorial; cost; efficacy study; experience; fundus imaging; heme oxygenase-1; improved; in vivo; in vivo Model; inflammatory marker; intravitreal injection; mouse model; nanoparticle; nanoparticle delivery; neovascularization; novel; novel therapeutic intervention; novel therapeutics; overexpression; pre-clinical; prevent; retinal damage; sodium iodate; standard care; success; uptake

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.

项目摘要 与年龄相关的黄斑变性（AMD）是美国失明的第三大主要原因，也是领导者之一 全球失明的原因。最初，由过量活性氧引起的炎症导致干燥AMD引起的干燥AMD 物种（ROS），无法治愈。当它发展为湿AMD时，该疾病的特征是异常 由血管内皮生长因子（VEGF）过多表达引起的漏水血管的生长，该因子（VEGF）的生长 永久损害视网膜，并导致严重的视力丧失。抗VEGF治疗是当前的标准 湿AMD的处理。但是，经常进行玻璃体内注射的要求与高有关 治疗成本，患者负担和并发症的风险，包括疼痛。这也没有解决 疾病早期阶段的炎症成分。有临床需要减少注射频率 并治疗引起疾病的潜在炎症。该项目的总体目的是开发和 验证可维持释放的可注射，可生物降解的刺激性纳米颗粒输送系统 几个月来治疗炎症的新治疗方法。在AIM 1中，研究性治疗将是 合成和表征。刺激反应性的聚多巴胺纳米颗粒，这些纳米颗粒在 活性氧（ROS）的存在将被合成并加载新的治疗方法。 将评估治疗性和纳米颗粒的体外细胞摄取 使用流式细胞仪的细胞。将评估治疗性和纳米颗粒的短期生物相容性 在2周内在小鼠模型中进行体内。在AIM 2中，拟议治疗的体内生物相容性和功效 将在2个月内在干燥AMD的钠碘钠钠钠钠钠钠酸钠模型中进行评估。结构和功能 眼睛的评估将包括眼内压，眼底成像，光谱结构域光学连贯性 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 同时。 2个月后，ELISA验证眼组织中的治疗浓度。 Elisa Will 还用于评估疾病模型中HO-1的视网膜表达水平，以研究 拟议的治疗作用。这些目标将评估ROS响应性药物输送系统以维持 眼睛中释放抗炎治疗。这具有治疗潜在疾病途径的潜力 与AMD相关并减少玻璃体内注射，改善AMD和AMD患者的生活质量 其他眼或炎症性疾病。