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Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic kidney disease worldwide, characterized by fluid-filled cyst growth and enlargement of both kidneys that leads to kidney failure. Despite the tremendous need and the hereditary nature of the disease, there are no treatments that intervene at early stages. Thus, in this Innovative Science Accelerator Program award, we propose a radically different approach and distinct scientific direction for ADPKD treatment and management: Engineering urinary extracellular vesicles as a novel and safe therapy that can treat early-stage ADPKD and thereby stop kidney failure. We will harness urinary extracellular vesicles which are known to be naturally loaded with polycystin-1 and polycystin-2, or gene products of PKD1 or PKD2 that are mutated in ADPKD, as endogenous nanotherapeutics that can enable protein and gene therapy. The surface of the extracellular vesicles will be engineered with ligands that home to renal epithelial cells that contribute to ADPKD at early stages. The homing, therapeutic, and safety of engineered urinary extracellular vesicles will be evaluated using in vitro and in vivo models of ADPKD. This technology represents a paradigm shift and departure from current small molecule drugs in ADPKD that cause off target toxicity with very modest benefit in delaying end stage kidney disease and can only target one downstream pathway, of many, that is affected by in ADPKD. Instead, our technology will develop a therapeutic strategy based on targeted, protein and gene therapy using engineered extracellular vesicles to supplement the genetic defect that causes ADPKD, making it both ambitious and transformative. The research proposal focuses on pushing technology development that cuts across the KUH communities making it ideally suited for the ISAC, and we will create a novel platform that can be adapted for other kidney disorders as well as pediatric and rare diseases.
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