Friday, May 9, 2025
5/9/2025
Extracellular vesicle-based intraocular therapy combined with active targeting of ocular neovascularization - Abstract (Parent Award) Intravitreal injection of anti-vascular endothelial growth factor (VEGF) agent monotherapy is the current mainstay for treating neovascular age-related macular degeneration (NVAMD). Despite its vision saving benefit, some patients fail to respond to the treatment because of insufficient therapeutic effect and/or the socioeconomic burden of frequently required repeat injections. Therefore, the long-term goal of our studies is to develop superior or adjunctive approaches to the current anti-VEGF therapy that can provide active targeting of NVAMD, have the capacity to deliver multiple drugs, and maintain long-term efficacy. Exosomes are naturally occurring, cell secreted, and nano-sized extracellular vesicles. Exosomes carry various cargos including microRNAs, proteins, and lipids for cell-to-cell communications. Recently, we have shown that intravitreally delivered ASL-exosomes composed of Anchor, Spacer, and Arg-Gly-Asp acid (RGD) Ligand-modification actively target choroidal neovascularization (CNV) with adequate retinal penetration. The unique nature of exosomes and our study demonstrate great promise in exosomes as the next regeneration intraocular drug delivery system. However, the accelerated translation to humans has been hindered due to a lack of clarity as to mechanisms of exosome uptake within the retina thus preventing a standardized formulation and an optimized therapeutic application of exosomes. The objective of the current studies is to elucidate the extracellular and intracellular mechanisms by which ASL-exosomes actively target ocular NV and to use this information in optimizing this drug delivery system for simultaneous delivery of Aflibercept and miR-24 to suppress ocular NV and its secondary fibrosis through independent pathways. Our proposed studies will test the hypothesis that intravitreally delivered ASL-exosomes allow their targeted delivery to ocular NV lesions through active binding to increasingly expressed transmembrane integrins at NV sites and through increased intracellular uptake of exosomes by integrin receptor-mediated intracellular endocytosis. Further, we hypothesize that the ASL-exosome system that is complemented with active targeting and sustained multi-drug delivery capacity with minimal immune responses can effectively suppress NV and fibrosis by co-delivering Aflibercept and miR-24, a new intracellular target for retinal fibrosis. The central hypothesis will be tested by pursuing three specific aims. Aim 1 is to determine the mechanism by which ASL-exosomes actively target ocular NV. Aim 2 is to optimize the formulation of multi- drugs loaded ASL-exosomes. Aim 3 is to determine sustained multi-drug delivery using exosomes and related immune responses. The research proposed in this application is innovative because the combination of an exosome-based intraocular drug delivery system with active targeting is a novel strategy that has the potential to change the current treatment paradigm from passive targeting-directed monotherapy to active targeting- directed multi-drug delivery with sustained efficacy for the treatment of various retinal and choroidal vascular diseases.
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