Extracellular Vesicle Therapy for Diabetic Retinopathy

细胞外囊泡治疗糖尿病视网膜病变

• 批准号: 10723000
• 负责人: Sun Young Lee
• 金额: $ 48.01万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 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/10723000
• 关键词: Acids; Address; Adhesions; Affect; Aftercare; Angiogenic Factor; Area; Binding; Biological Products; Blindness; Blood Vessels; Cell Communication; Cell secretion; Cells; Choroidal Neovascularization; Clinical; Complement; Control Groups; Deterioration; Development; Diabetes Mellitus; Diabetic Retinopathy; Diameter; Disease; Early treatment; Economic Burden; Engineering; Epigenetic Process; Extravasation; Fibrosis; Fostering; Functional disorder; Genes; Glucose; Goals; Homeostasis; Hypoxia; Immune; Inflammation; Injections; Integrins; Label; Leukocytes; Ligands; Light Coagulation; Macrophage; Metabolic; MicroRNAs; Modeling; Modification; Muller' s cell; Neuroglia; Neurons; Oxygen; Pathologic; Pathway interactions; Patients; Penetration; Persons; Physiological; Play; Population; Process; Progressive Disease; Public Health; RGD (sequence); Research; Retina; Retinal Diseases; Retinal Neovascularization; Risk Factors; Role; Site; Source; Steroids; Streptozocin; Stress; Subgroup; System; Testing; Therapeutic Agents; Vascular Diseases; Vascular Permeabilities; Vision; Visual impairment; age group; angiogenesis; bevacizumab; biomaterial compatibility; cell type; diabetes management; diabetic; early screening; efficacy testing; exosome; extracellular vesicles; glial activation; innovation; laser photocoagulation; macular edema; molecular targeted therapies; mouse model; nanosized; neovascularization; neuroprotection; neurovascular; neurovascular unit; novel strategies; novel therapeutic intervention; novel therapeutics; prevent; recruit; retinal angiogenesis; socioeconomics; stem cells; targeted delivery; translational applications; treatment strategy; uptake

PROJECT SUMMARY Diabetic retinopathy (DR) is a leading cause of severe vision loss, affecting nearly 100 million people globally and over 4 million in the US. Long-standing microangiopathy-driven diabetic macular edema (DME) and retinal neovascularization (NV) are the major causes of severe vision loss in advanced stages of DR. Thus, inhibition of aberrant angiogenic factors using an injection of anti-VEGF, steroid, or laser photocoagulation therapy is the current mainstay for treating advanced DR, however, often fail to resume vision. Since DR remains asymptomatic until the disease is significantly advanced, screening of early DR and tight control of modifiable systemic risk factors is a current strategy to manage the early stages of DR. Therefore, developing treatment directly addressing early pathologic changes in DR, thus preventing visual impairment is a significant unmet need. More recent studies indicate that diabetes injures the retinal neurovascular unit (NVU) and its interdependent vascular, neuronal, glial, and immune cells during the development of DR. The long-term goal of our studies is to develop a new treatment strategy to realign the disrupted neurovascular microenvironment in DR that protects the retina and visual function. The overall objectives of this application are to test two treatment strategies in DR that complement each other: 1) active targeting of DR that allows targeted delivery of therapeutic agents to the areas of retinal vascular dysfunction in its various stages, and 2) intraocular Müller glia-derived exosome treatment to modulate microenvironment of NVU. Recently, we have shown that exosomes decorated with ASL (ASL-Exo), composed of Anchor, Spacer, and Arg-Gly-Asp acid (RGD) Ligand-modification actively targets choroidal neovascularization (CNV). RGD is one of the major ligands and specifically binds a subgroup of integrins that play an essential role in retinal inflammation, vascular leakage, angiogenesis, and fibrosis in DR. Further, Müller glia is a major source of neuroprotective and vascular permeability factors, antioxidative activity and epigenetic modulators. The central hypothesis of this proposal is that bioactive molecules contained in Müller glia-derived exosomes promote homeostasis of NVU in DR. The central hypothesis will be tested by pursuing two specific aims. Aim 1 is to evaluate the targeted distribution of intravitreally delivered ASL-Exo to dysfunctional retinal vasculature in DR. Aim 2 is to determine whether Müller glia-derived ASL-Exo (Müller-ASL-Exo) suppresses DR by protecting the retina from microangiopathy, inflammation, glial activation, and NV formation and epigenetic alternation within the retina. The research proposed in this application will test an innovative and novel strategy that has a great potential to change the current treatment paradigm from passive targeting-directed monotherapy to active targeting-directed multimolecular target for the treatment of various stages of DR.

项目概要 糖尿病视网膜病变 (DR) 是导致严重视力丧失的主要原因，影响全球近 1 亿人 美国有超过 400 万人患有长期微血管病导致的糖尿病性黄斑水肿 (DME) 和视网膜。 新生血管形成（NV）是 DR 晚期严重视力丧失的主要原因，因此，抑制。 使用注射抗 VEGF、类固醇或激光光凝疗法来治疗异常的血管生成因子是 然而，目前治疗晚期 DR 的主要方法往往无法恢复视力，因为 DR 仍然无症状。 直到疾病明显进展，筛查早期 DR 并严格控制可改变的系统性风险 因此，直接开发治疗方法是当前管理 DR 早期的策略。 解决 DR 的早期病理变化，从而预防视力障碍是一个未得到满足的重大需求。 最近的研究表明，糖尿病会损伤视网膜神经血管单元（NVU）及其相互依赖的血管， 我们研究的长期目标是开发 DR 发展过程中的神经元、胶质细胞和免疫细胞。 一种新的治疗策略，可以重新调整 DR 中受损的神经血管微环境，从而保护视网膜 该应用程序的总体目标是测试 DR 的两种治疗策略： 相辅相成：1) 主动靶向 DR，允许将治疗药物靶向递送至相关区域 不同阶段的视网膜血管功能障碍的研究，以及 2) 眼内 Müller 胶质细胞来源的外泌体治疗 最近，我们发现用 ASL (ASL-Exo) 修饰的外泌体， 由锚定基团、间隔基团和精氨酸-甘氨酸-天冬氨酸 (RGD) 配体修饰组成，主动靶向脉络膜 新生血管 (CNV) 是主要配体之一，特异性结合整合素亚组。 Müller 进一步指出，在 DR 的视网膜炎症、血管渗漏、血管生成和纤维化中发挥着重要作用。 神经胶质细胞是神经保护和血管通透性因子、抗氧化活性和表观遗传的主要来源 该提议的中心假设是穆勒神经胶质细胞中含有的生物活性分子。 外泌体促进 DR 中 NVU 的稳态 我们将通过两个具体的研究来检验中心假设。 目标 1 是评估玻璃体内递送的 ASL-Exo 对功能障碍视网膜的靶向分布。 目标 2 是确定 Müller 胶质细胞衍生的 ASL-Exo (Müller-ASL-Exo) 是否抑制 DR。 通过保护视网膜免受微血管病变、炎症、神经胶质活化、NV 形成和表观遗传的影响 本申请中提出的研究将测试一种创新的策略。 具有改变当前被动靶向单一疗法的治疗模式的巨大潜力 主动靶向多分子靶点治疗不同阶段的 DR。