Targeting the ADPKD methylome using nanoparticle-mediated combination therapy.

Autor:	Trinh A, Huang Y; Department of Biomedical Engineering, University of Southern California, Los Angeles, California 90089, USA., Shao H, Ram A; Department of Biomedical Engineering, University of Southern California, Los Angeles, California 90089, USA., Morival J, Wang J; Department of Biomedical Engineering, University of Southern California, Los Angeles, California 90089, USA., Chung EJ, Downing TL
Jazyk:	angličtina
Zdroj:	APL bioengineering [APL Bioeng] 2023 Jun 09; Vol. 7 (2), pp. 026111. Date of Electronic Publication: 2023 Jun 09 (Print Publication: 2023).
DOI:	10.1063/5.0151408
Abstrakt:	DNA methylation aberrancies are found in autosomal dominant polycystic kidney disease (ADPKD), which suggests the methylome to be a promising therapeutic target. However, the impact of combining DNA methylation inhibitors (DNMTi) and ADPKD drugs in treating ADPKD and on disease-associated methylation patterns has not been fully explored. To test this, ADPKD drugs, metformin and tolvaptan (MT), were delivered in combination with DNMTi 5-aza-2'-deoxycytidine (Aza) to 2D or 3D cystic Pkd1 heterozygous renal epithelial cells (PKD1-Het cells) as free drugs or within nanoparticles to enable direct delivery for future in vivo applications. We found Aza synergizes with MT to reduce cell viability and cystic growth. Reduced representation bisulfite sequencing (RRBS) was performed across four groups: PBS, Free-Aza (Aza), Free-Aza+MT (F-MTAza), and Nanoparticle-Aza+MT (NP-MTAza). Global methylation patterns showed that while Aza alone induces a unimodal intermediate methylation landscape, Aza+MT recovers the bimodality reminiscent of somatic methylomes. Importantly, site-specific methylation changes associated with F-MTAza and NP-MTAza were largely conserved including hypomethylation at ADPKD-associated genes. Notably, we report hypomethylation of cancer-associated genes implicated in ADPKD pathogenesis as well as new target genes that may provide additional therapeutic effects. Overall, this study motivates future work to further elucidate the regulatory mechanisms of observed drug synergy and apply these combination therapies in vivo . Competing Interests: The authors have no conflicts to disclose. (© 2023 Author(s).)
Databáze:	MEDLINE
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