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Kidney Week

Abstract: TH-PO687

RGLS4326 Confers Efficacy and Modulate Aberrant Signaling and Metabolic Pathways in PKD Mouse Models

Session Information

Category: Genetic Diseases of the Kidney

  • 1001 Genetic Diseases of the Kidney: Cystic

Authors

  • Valencia, Tania M., Regulus Therapeutics Inc, San Diego, California, United States
  • Gatto, Sole, Regulus Therapeutics Inc, San Diego, California, United States
  • Schairer, Annelie E., Regulus Therapeutics Inc, San Diego, California, United States
  • Lockton, Steven, Regulus Therapeutics Inc, San Diego, California, United States
  • Kim, Michael, Regulus Therapeutics Inc, San Diego, California, United States
  • Kersjes, Kara, Regulus Therapeutics Inc, San Diego, California, United States
  • Li, Jian, Regulus Therapeutics Inc, San Diego, California, United States
  • Flaten, Andrea N., University of Texas Southwestern Medical Center, Dallas, Texas, United States
  • Patel, Vishal, University of Texas Southwestern Medical Center, Dallas, Texas, United States
Background

Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in PKD1 and PKD2 genes, where expansion of fluid-filled cysts and renal fibrosis often leads to end-stage renal disease. MicroRNAs are short non-coding RNAs that modulate several biological processes. We have previously shown that aberrant expression of miR-17 family of microRNAs is involved in human ADPKD pathogenesis. RGLS4326 is a chemically-modified oligonucleotide designed to sterically inhibit miR-17 functions and has been shown to reduce cyst growth in vitro and in vivo. The goal of this study was to determine the signaling pathways modulated by RGLS4326 treatment in PKD mouse models

Methods

RGLS4326 is efficacious in the Pkd2-KO and Pcy mouse models of PKD. We performed RNA sequencing and metabolite profiling using kidney samples from both mouse models following RGLS4326 treatment. Ingenuity Pathway Analysis was used to provide novel insights into signaling pathways modulated by RGLS4326 treatment.

Results

Through RNA sequencing, we identified >10000 differentially expressed genes in the PKD kidney samples compared to their age- and strain-matched normal controls. Comparative pathway analysis identified several dysregulated signaling pathways in the two PKD mouse models, including the Pparα, WNT/ β-catenin and cell cycle signaling, that were in turn modulated following RGLS4326 treatment.
Next, we performed global metabolite profiling comparing Pkd2-KO and normal kidneys, and identified several biochemical alterations in the Pkd2-KO model, including substantial changes in lipid metabolism. In particular, decrease in β-fatty acid oxidation pathway was observed in the Pkd2-KO kidneys, which corroborates with previously observed Pparα-dysregulation in PKD mouse models. Importantly, modulation in lipid metabolites were also observed following RGLS4326 treatment.

Conclusion

Our results indicate that RGLS4326 confers efficacy and modulate aberrant PKD signaling and metabolic pathways. RGLS4326 is currently in Phase I clinical studies for the treatment of ADPKD.

Funding

  • Commercial Support