Abstract: TH-PO0046
Targeting Dysregulated Epigenetic Modifiers with Kidney-Targeted Nanotherapeutics for PKD
Session Information
- Bioengineering: MPS, Flow, and Delivery
November 06, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Bioengineering
- 400 Bioengineering
Authors
- Giblin, Joshua, University of Southern California, Los Angeles, California, United States
- Chung, Eun ji, University of Southern California, Los Angeles, California, United States
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.