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 糖尿病性视网膜病（DR）是造成严重视力丧失的主要原因，全球影响近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 新血管化（NV）是DR的晚期阶段严重视力丧失的主要原因。那，抑制 使用抗VEGF，类固醇或激光光凝治疗的异常血管生成因子是 但是，目前用于治疗高级DR的主要支柱通常无法恢复视力。由于DR无症状 直到疾病明显晚期为止，筛查早期DR和严格控制可修改的全身风险 因素是管理DR的早期阶段的当前策略。因此，直接开发治疗 解决DR的早期病理变化，因此防止视觉障碍是一个重大的未满足需求。更多的 最近的研究表明，糖尿病损伤了残留神经血管单元（NVU）及其相互依存的血管， DR开发过程中神经元，神经胶质和免疫细胞。我们研究的长期目标是发展 一种新的治疗策略，以重新调整DR中破坏的神经血管微环境，以保护视网膜 和视觉功能。该应用程序的总体目标是测试DR中的两种治疗策略 彼此完成：1）DR的主动靶向，该靶向允许将治疗剂靶向到该区域 在其各个阶段的视网膜血管功能障碍，以及2）眼内müller胶质衍生的外泌体治疗 调节NVU的微环境。最近，我们已经表明，用ASL（ASL-EXO）装饰的外泌体， 由锚固，垫片和arg-gly-asp酸（RGD）组成的配体修饰主动针对脉络膜 新血管形成（CNV）。 RGD是主要配体之一，专门绑定了整合素的亚组 DR中的视网膜注射，血管泄漏，血管生成和纤维化起着至关重要的作用。此外，穆勒 神经胶质是神经保护性和血管通透性因子，抗氧化活性和表观遗传学的主要来源 调节器。该提议的中心假设是穆勒胶质衍生的生物活性分子 外泌体在DR中促进NVU的体内平衡。中心假设将通过追求两个特定的 目标。 AIM 1是评估玻璃体内部ASL-EXO的靶向分布到功能失调的视网膜 脉管系统AIM 2是确定MüllerGlia衍生的ASL-EXO（müller-asl-exo）是否抑制DR 通过保护视网膜免受微型疾病，注射，神经胶质激活和NV形成和表观遗传学 视网膜内的替代方案。本应用程序中提出的研究将测试一种创新和新颖的策略 这具有从被动靶向单一疗法中改变当前治疗范式的巨大潜力 进行主动靶向定向的多分子靶标，以治疗DR的各个阶段。