Synergistic treatment of genetic kidney disease with DNA methylation inhibitors
Synergistic treatment of genetic kidney disease with DNA methylation inhibitors lead image
About 12 million people worldwide have autosomal dominant polycystic kidney disease (ADPKD), a genetic disorder in which fluid-filled cysts form in the kidneys, leading to kidney failure. However, both tolvaptan, the only FDA-approved drug for ADPKD, and metformin, an investigative ADPKD drug, exhibit side effects and only modestly slow disease progression.
Trinh et al. investigated an alternative strategy to treat ADPKD. DNA methylation aberrancies are found in cells affected by ADPKD, which suggests targeting methylation could help treat this disease.
This collaboration between epigenetic engineering and ADPKD nanomedicine experts combined metformin and tolvaptan with the DNA methylation inhibitor 5-aza-2’-deoxycytidine (Aza) and delivered this drug combo to cystic kidney cells. The authors found the ADPKD drugs synergize with Aza to induce DNA hypomethylation and reduce ADPKD cell proliferation and cyst growth in vitro.
These results suggest this synergistic strategy might be better able to treat this disease than existing ADPKD drugs alone. As a secondary benefit, some genes targeted by the drugs are also associated with cancer.
“Our study identifies potential novel therapeutic targets for ADPKD, which show overlap in genes involved in both ADPKD and cancer,” said author Timothy Downing.
Delivering the drugs within nanoparticles conserved their effects on methylation and target cyst growth, reducing off-target effects. Nanoparticles may be able to deliver these drugs directly to kidneys in vivo.
“Future studies will determine the therapeutic effects of drug combinations in vivo, where we believe the advantages of our nanoparticle will be most pronounced,” said author Eun Ji Chung.
The authors also plan to further study the underlying regulatory mechanisms, including how methylation changes affect ADPKD processes.
Source: “Targeting the ADPKD methylome using nanoparticle-mediated combination therapy,” by Annie Trinh, Yi Huang, Hanjuan Shao, Aparna Ram, Julien Morival, Jonathan Wang, Eun Ji Chung, and Timothy L. Downing, APL Bioengineering (2023). The article can be accessed at https://doi.org/10.1063/5.0151408 .
