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Abstract: TH-PO686

Efficacy of RGLS4326 in Human Primary ADPKD 3D-Cyst Cultured Cells

Session Information

Category: Genetic Diseases of the Kidney

  • 1001 Genetic Diseases of the Kidney: Cystic


  • Schairer, Annelie E., Regulus Therapeutics, San Diego, California, United States
  • Valencia, Tania M., Regulus Therapeutics, San Diego, California, United States
  • Lockton, Steven, Regulus Therapeutics, San Diego, California, United States
  • Gatto, Sole, Regulus Therapeutics, San Diego, California, United States
  • Kim, Michael, Regulus Therapeutics, San Diego, California, United States
  • Wallace, Darren P., University of Kansas Medical Center, Kansas City, Kansas, United States
  • Lee, Edmund, Regulus Therapeutics, San Diego, California, United States

Autosomal dominant polycystic kidney disease (ADPKD), caused by mutations in the PKD1 or PKD2 gene, is among the most common monogenetic disorders and a leading genetic cause of end-stage renal disease. Kidney-specific overexpression of miR-17~92 produce kidney cysts in mice, whereas genetic knockdown of miR-17~92 attenuates disease progression in multiple mouse models of PKD. RGLS4326 is designed to specifically bind to miR-17 family of microRNAs, antagonize miR-17 activity and reduce disease progression in mouse models of PKD. In this study, we investigate the effect of RGLS4326 treatment on 3D growth of human primary ADPKD cyst cells derived from ADPKD donor nephrectomy samples.


Primary human ADPKD cyst cells (HuADPKD) were transfected with RGLS4326 or control oligo at 20nM, 100nM or 300nM for 24h. RNA samples were harvested for confirmation of miR-17 inhibition by measuring de-repression of a selected set of direct miR-17 target genes (PD-Sig) and RNA sequencing. Cells following 24h transfection were then seeded and further cultured in 3D cyst formation assay for 8 additional days.


Functional inhibition of miR-17 in HuADPKD following RGLS4326 treatment was confirmed by PD-Sig. At the end of 8 additional days of 3D culturing, RGLS4326 consistently reduced growth of HuADPKD derived from multiple donors, decreasing cyst count and proliferation. Kolmogorov-Smironov test statistics on RNA sequencing data comparing log2FC cumulative distribution indicated significant upregulation (i.e. de-repression) of predicted miR-17 target genes after RGL4326 treatment. De-repression of selected direct miR-17 target genes were confirmed by qPCR and their implication on RGLS4326’s mechanism of action in conferring efficacy were investigated.


RGLS4326 inhibits 3D cyst formation and growth of HuADPKD cells in vitro compared to oligo control. Our preclinical data supports the clinical development of RGLS4326 which is currently in Phase 1 for the treatment of ADPKD.


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