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.

项目概要 年龄相关性黄斑变性 (AMD) 是美国第三大失明原因，也是导致失明的主要原因之一 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 种（ROS），并且无法治愈。当进展为湿性 AMD 时，该疾病的特征是异常 血管内皮生长因子（VEGF）过度表达导致渗漏血管生长， 永久性损害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要求与高 治疗费用、患者负担以及疼痛等并发症的风险。这也没有解决 疾病早期阶段的炎症成分。临床需要减少注射频率 并治疗引起疾病的潜在炎症。该项目的总体目标是开发和 验证可持续释放的可注射、可生物降解、刺激响应的纳米颗粒递送系统 一种可以治疗炎症几个月的新疗法。在目标 1 中，研究性治疗将是 合成并表征。刺激响应型聚多巴胺纳米颗粒可释放更多治疗作用 活性氧（ROS）的存在将被合成并加载到新的治疗剂中。 将评估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 使用流式细胞仪检测细胞。将评估治疗剂和纳米颗粒的短期生物相容性 在小鼠模型体内进行了两周的体内实验。在目标 2 中，所提出的治疗方法的体内生物相容性和功效 将在干性 AMD 的碘酸钠小鼠模型中进行为期 2 个月的评估。结构和功能 眼睛评估包括眼压、眼底成像、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。眼组织中的治疗浓度将在 2 个月后通过 ELISA 进行验证。酶联免疫吸附试验将 也可用于评估疾病模型中HO-1的视网膜表达水平，以研究其机制 拟议治疗的作用。这些目标将评估 ROS 响应药物输送系统，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 与 AMD 相关并减少玻璃体内注射，改善 AMD 患者的生活质量 其他眼部或炎症性疾病。