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.

项目摘要 糖尿病视网膜病变（DR）是严重视力丧失的主要原因，影响全球近1亿人 在美国超过400万。长期存在的微血管病驱动的糖尿病性黄斑水肿（DME）和视网膜病变 新生血管（NV）是DR晚期严重视力丧失的主要原因。 使用注射抗VEGF、类固醇或激光光凝治疗的异常血管生成因子是 然而，目前用于治疗晚期DR的主要药物通常不能恢复视力。由于DR仍无症状 直到疾病显著进展，筛查早期DR并严格控制可改变的系统性风险 因素是当前管理DR早期阶段的策略。因此，直接开发治疗方法 解决DR中的早期病理变化，从而预防视力损害是一个显著未满足的需求。更 最近的研究表明糖尿病损害视网膜神经血管单元（NVU）及其相互依赖的血管， 神经元，神经胶质细胞和免疫细胞在DR的发展。我们研究的长期目标是发展 一种新的治疗策略，重新调整DR中被破坏的神经血管微环境，保护视网膜 和视觉功能。本申请的总体目标是测试DR中的两种治疗策略， 相互补充：1）DR的主动靶向，其允许将治疗剂靶向递送至 视网膜血管功能障碍的不同阶段，和2）眼内Müller胶质源性外泌体治疗， 调节NVU微环境。最近，我们已经证明了用ASL修饰的外泌体（ASL-Exo）， 由锚、间隔和Arg-Gly-Asp酸（RGD）组成 新生血管形成（CNV）。RGD是主要配体之一，并特异性结合整合素亚组， 在DR的视网膜炎症、血管渗漏、血管生成和纤维化中发挥重要作用。 神经胶质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。 调制器。这一建议的中心假设是，Müller胶质源性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。 目标。目的1是评估玻璃体内递送的ASL-Exo在功能障碍性视网膜病变中的靶向分布。 目的2是确定Müller胶质源性ASL-Exo（Müller-ASL-Exo）是否抑制DR 通过保护视网膜免受微血管病、炎症、神经胶质活化和NV形成和表观遗传 视网膜内的交替。本申请中提出的研究将测试一种创新和新颖的策略 这有很大的潜力改变目前的治疗模式，从被动靶向单一治疗， 涉及用于治疗DR的各个阶段的主动靶向多分子靶向。