Extracellular Vesicle Therapy for Diabetic Retinopathy

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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.