2. Academic Validation
  3. Targeting Dysregulated Epigenetic Modifiers With Kidney-Targeted Nanotherapeutics for Polycystic Kidney Disease

Targeting Dysregulated Epigenetic Modifiers With Kidney-Targeted Nanotherapeutics for Polycystic Kidney Disease

  • J Biomed Mater Res A. 2025 Apr;113(4):e37909. doi: 10.1002/jbm.a.37909.
Joshua Giblin 1,  Rowan Simon 1,  Jose Zarate-Diaz 1,  Brenton Lee 1,  Eun Ji Chung 1 2 3 4 5 6 7
Affiliations

Affiliations

  • 1 Alfred E. Mann Department of Biomedical Engineering, University of Southern California, Los Angeles, California, USA.
  • 2 Department of Medicine, Division of Nephrology and Hypertension, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
  • 3 Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, California, USA.
  • 4 Department of Surgery, Division of Vascular Surgery and Endovascular Therapy, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
  • 5 Department of Stem Cell Biology and Regenerative Medicine, University of Southern California, Los Angeles, California, USA.
  • 6 Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, USA.
  • 7 Bridge Institute, University of Southern California, Los Angeles, California, USA.
PMID: 40200735 DOI: 10.1002/jbm.a.37909
Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic kidney disease worldwide. The one small molecule drug available to patients, tolvaptan, is associated with off-target side effects and high discontinuation rates, necessitating the development of new therapeutic strategies. Previous work has shown that the epigenome is altered in ADPKD; however, the identification and targeting of dysregulated epigenetic modulators has yet to be explored for human ADPKD therapy. Using cells derived from cysts of ADPKD patients, we tested the gene expression of several epigenetic modulators. We found Brd4 and BMI1 are upregulated and observed that their inhibition using small molecule drugs, AZD-5153 and PTC-209, significantly slowed the proliferation of ADPKD patient cells. To enhance the delivery of AZD-5153 and PTC-209 to renal cells, we loaded the drugs into kidney-targeting micelles (KM) and assessed their therapeutic effects in vitro. Combining AZD-5153 and PTC-209 in KMs had a synergistic effect on reducing the proliferation in ADPKD patient cells and in a 3D PKD cyst model. These findings were also consistent in murine in vitro models using PKD1 null renal proximal tubule cells. In summary, we demonstrate Brd4 and BMI1 as novel targets in ADPKD and targeting the epigenome using kidney nanomedicine as a novel therapeutic strategy in ADPKD.

Keywords

ADPKD; chronic kidney disease; drug delivery; epigenetics; nanomedicine.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z