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Kidney Week

Abstract: TH-PO685

Discovery and Preclinical Characterization of RGLS4326 for the Treatment of Autosomal Dominant Polycystic Kidney Disease (ADPKD)

Session Information

Category: Genetic Diseases of the Kidney

  • 1001 Genetic Diseases of the Kidney: Cystic

Authors

  • Lee, Edmund, Regulus Therapeutics, San Diego, California, United States
  • Valencia, Tania M., Regulus Therapeutics, San Diego, California, United States
  • Schairer, Annelie E., Regulus Therapeutics, San Diego, California, United States
  • Kersjes, Kara, Regulus Therapeutics, San Diego, California, United States
  • Li, Jian, Regulus Therapeutics, 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), caused by mutations in the PKD1 or PKD2 genes, is among the most common human monogenetic disorders and a leading genetic cause of end-stage renal disease (ESRD). MicroRNAs (miRs) are non-coding RNAs that play central roles in cell differentiation, proliferation and survival by binding to complementary target mRNAs, resulting in repression of translation and eventual degradation of the targeted mRNAs. We have previously demonstrated that miR-17 promotes ADPKD progression, and inhibiting miR-17 is a promising strategy for the treatment of ADPKD.

Methods

RGLS4326 was discovered through screening a chemically-diverse library of >100 oligonucleotides for their ability to inhibit miR-17 in a miR-17 luciferase sensor assay. RGLS4326 was extensively profiled in multiple safety assays, including biochemical, ex-vivo tissues slices and in vivo studies. Preclinical efficacy of RGLS4326 was studied in both Pkd2-KO and Pcy mouse models of PKD.

Results

In preclinical studies, RGLS4326 potently inhibited miR-17 activity, displaced miR-17 from the translationally active high molecular weight polysomes, and de-repressed multiple miR-17 target genes in different mouse kidney cell lines. RGLS4326 shows favorable pharmacokinetic profiles in both normal and PKD mouse models, where preferential distribution to kidney compare to other tissues was evident. Most importantly, we have demonstrated that RGLS4326 confers efficacy in two mouse models of PKD following subcutaneous administrations.

Conclusion

Our preclinical data support the clinical development of RGLS4326 for the treatment of ADPDK. RGLS4326 is currently being studied in Phase I clinical studies.

Funding

  • Commercial Support