Giblin Joshua, Simon Rowan, Zarate-Diaz Jose, Lee Brenton, Chung Eun Ji
Alfred E. Mann Department of Biomedical Engineering, University of Southern California, Los Angeles, California, USA.
Department of Medicine, Division of Nephrology and Hypertension, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
J Biomed Mater Res A. 2025 Apr;113(4):e37909. doi: 10.1002/jbm.a.37909.
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.
常染色体显性多囊肾病（ADPKD）是全球最常见的遗传性肾病。患者可用的一种小分子药物托伐普坦存在脱靶副作用且停药率高，因此需要开发新的治疗策略。先前的研究表明，ADPKD患者的表观基因组发生了改变；然而，对于人类ADPKD治疗，失调的表观遗传调节剂的鉴定和靶向作用尚未得到探索。我们使用源自ADPKD患者囊肿的细胞，检测了几种表观遗传调节剂的基因表达。我们发现Brd4和BMI1上调，并观察到使用小分子药物AZD - 5153和PTC - 209抑制它们可显著减缓ADPKD患者细胞的增殖。为提高AZD - 5153和PTC - 209向肾细胞的递送，我们将药物负载到肾脏靶向胶束（KM）中，并评估它们在体外的治疗效果。在KM中联合使用AZD - 5153和PTC - 209对降低ADPKD患者细胞和三维PKD囊肿模型中的细胞增殖具有协同作用。这些发现在用Pkd1基因敲除的肾近端小管细胞构建的小鼠体外模型中也得到了证实。总之，我们证明Brd4和BMI1是ADPKD中的新靶点，并将肾脏纳米药物作为ADPKD的一种新治疗策略用于靶向表观基因组。
