Extracellular Vesicle Therapy for Diabetic Retinopathy

项目总结 糖尿病视网膜病变(DR)是导致严重视力丧失的主要原因，全球有近1亿人受到影响 在美国有超过400万人。长期存在的微血管病变导致的糖尿病黄斑水肿(DME)和视网膜 新生血管(NV)是DR晚期严重视力丧失的主要原因。 使用抗血管内皮生长因子注射、类固醇或激光光凝治疗的异常血管生成因子是 然而，目前治疗晚期DR的主要手段往往无法恢复视力。由于DR仍无症状 在疾病显著进展之前，对早期DR进行筛查，并严格控制可改变的系统性风险 因素是目前管理DR早期阶段的一种策略，因此，直接开发治疗方法 解决糖尿病视网膜病变的早期病理变化，从而预防视力损害是一个重要的未得到满足的需求。更多 最近的研究表明，糖尿病损害了视网膜神经血管单位(NVU)及其相互依赖的血管， 神经细胞、神经胶质细胞和免疫细胞在DR的发育过程中我们研究的长期目标是发展 重新调整糖尿病视网膜病变的神经血管微环境以保护视网膜的新治疗策略 和视觉功能。本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，允许有针对性地将治疗剂输送到该地区 视网膜血管功能障碍的不同阶段，以及2)眼内Müller神经胶质细胞来源的外切体治疗 调节NVU的微环境。最近，我们发现用ASL(ASL-Exo)修饰的外切体， 由锚定、间隔物和精氨酸-甘氨酸-天冬氨酸(RGD)组成的配体修饰活性靶向脉络膜 新生血管(CNV)。RGD是主要的配体之一，它特异性地结合整合素的一个亚群 在视网膜炎症、血管渗漏、血管生成和纤维化中发挥重要作用 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学的主要来源。 调制器。这一提议的中心假设是，穆勒胶质细胞中含有的生物活性分子源于 外切体促进NVU在DR中的动态平衡中心假说将通过追求两个特定的 目标。目的1：评价ASL-Exo玻璃体内给药对功能障碍视网膜的靶向分布 博士2的脉管学研究目的是确定穆勒胶质细胞来源的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、胶质细胞激活、新生血管形成和表观遗传学的影响 视网膜内的交替。这项申请中提出的研究将测试一种创新和新颖的策略 这极有可能改变目前的治疗模式，从被动靶向导向的单一疗法 以主动靶向为导向的多分子靶点治疗不同阶段的DR

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.