Targeting Dysregulated Epigenetic Modifiers with Kidney-Targeted Nanotherapeutics for PKD

Background: Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic kidney disease globally. Currently, tolvaptan, is the only FDA-approved therapy. However, its limited efficacy and off-target effects highlight the urgent need for more effective and targeted treatments. Emerging evidence implicates epigenetic dysregulation in ADPKD pathogenesis, yet epigenome-targeted therapies remain largely unexplored. To address this, we screened a library of epigenetic modulators in patient-derived ADPKD renal cells and identified significant upregulation of Brd4 and BMi1. To improve kidney-specific delivery, we encapsulated the small molecule inhibitors AZD-5153 (Brd4 inhibitor) and PTC-209 (BMi1 inhibitor) into kidney-targeting micelles (KMs) and evaluated their efficacy in human and murine ADPKD models. Methods: Gene expression of epigenetic modulators was assessed by RT-qPCR in primary renal cells isolated from cysts of four ADPKD patients and from tissue of two healthy kidneys. The antiproliferative effects of AZD-5153 and PTC-209 were quantified using MTS assays. Both drugs were encapsulated into kidney-targeting peptide amphiphile micelles by lipid film hydration. Drug-loaded KMs were evaluated for their effects on cell proliferation and cyst growth using MTS assays and cyst diameter measurements after 48 hours of treatment. Results: We identified Brd4 and BMi1 as differentially expressed epigenetic regulators in ADPKD patient cells and observed a dose-dependent response in proliferation after incubation with AZD-5153 and PTC-209. Combination drug-loaded KMs exerted a synergistic effect in reducing proliferation and cyst growth in ADPKD patient-derived cells. We also observed that combination therapy with AZD-5153 and PTC-209 in KMs significantly reduced the proliferation of mouse Pkd1-null cells and cyst growth, demonstrating cross-species consistency. Hence, we show the potential of inhibiting Brd4 and BMi1 for ADPKD therapy and the enhanced therapeutic effects through nanoparticle delivery. Conclusion: We identified the epigenome as a therapeutic target for ADPKD and evaluated the efficacy of inhibiting Brd4 and BMi1 in ADPKD. We observed improved response upon loading inhibitors of the dysregulated epigenetic regulators into kidney-targeting nanoparticles and present a novel nanomedicine-based combinatorial therapeutic approach for ADPKD.