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Acute kidney injury (AKI) is a significant public health problem leading to 1.7 million deaths per year globally. Therapeutic interventions for AKI are lacking and primarily rely on supportive therapy or, in severe cases, renal replacement therapy. AKI pre-disposes individuals to developing chronic kidney disease and end stage renal failure. We aim to develop a novel therapeutic platform to mitigate AKI using engineered extracellular vesicles (eEVs) to deliver therapeutic cargo directly to the kidney proximal tubule. The key innovations to this approach compared to traditional EV-based approaches are engineering of donor cells to produce EVs with a KIM1 targeting peptide to promote delivery to the injured kidney, engineering EVs to carry therapeutic cargo that protects against proximal tubule injury and designing cargo with a proximal tubule specific promoter to limit activity to proximal tubule epithelial cells and reduce systemic side effects. This approach has the potential to circumvent many of the technical hurdles to implementing EV-based therapy including poor tissue-specific targeting, heterogeneous and poorly defined cargo, and off-target effects of systemic EV delivery. We have identified multiple potential therapeutic targets for different phases of AKI and AKI-CKD transition. Targets for AKI include cell survival factors (SOX9 and SOX11) and anti-inflammatory factors (IL-10 and NRF2) for the acute phase of injury and pro-regenerative factors (FOXM1 and HNF4A) to mitigate AKI to CKD transition. We aim to develop a pipeline for eEV production and characterization, perform in vitro and in vivo studies to determine if eEVs target proximal tubule cells after injury, and evaluate therapeutic potential in mouse models of AKI at different phases of injury. If successful, this approach represents a novel therapeutic strategy that has never been attempted for treatment of AKI that has potential to both preserve renal function after injury and minimize off-target deleterious effects of treatment.
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