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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, leading to kidney failure. Despite the tremendous need, there is only one clinically approved treatment, and it is limited by poor efficacy and dose-limiting toxicities. Although preclinical studies with investigational drugs have yielded promising results, they ultimately fail at the clinical level, highlighted most recently in the early termination of the phase III FALCON trial in which bardoxolone methyl had no delay to end-stage renal disease relative to placebo treatments. The failure of these seemingly promising drug candidates in humans stems from the inability of common murine models to recapitulate human physiology and ADPKD, resulting in poor translational strength and predictive power when evaluating investigational drugs. In addition, although there have been significant advancements in the management of diseases like cancer from the utilization of novel gene therapy and nanomedicine approaches, ADPKD management is decades behind in that it is focused on monotherapeutic small molecule drugs. Thus, in this Innovative Science Accelerator Program award, we propose a radically different approach for the management of ADPKD and the preclinical evaluation of investigational drugs: nanoparticle-mediated combination gene therapy validated through a porcine ADPKD model. We will engineer nanoparticles functionalized with kidney-targeting peptides to facilitate the co-delivery of siRNAs targeted to TMEM16a and MCP1, both of which are overexpressed in ADPKD and promote disease progression through CFTR-dependent chloride secretion and inflammation, respectively. This concept is paradigm-shifting and represents a departure in the conventional management of ADPKD in that it leverages a nanomedicine-mediated combination gene therapy approach to simultaneously target multiple dysregulated pathways in ADPKD, and importantly, the efficacy of this technology will be validated using a clinically relevant porcine model of ADPKD. The proposed research will develop a novel kidney-targeting nanoparticle platform that can be utilized to accelerate investigational drug screening for other kidney diseases of interest to the KUH communities, making it well-suited to the ISAC award.
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