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

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.