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Abstract: TH-PO408

Discovery of Next-Generation Anti-miR-17 Oligonucleotide RGLS8429 for Treatment of Autosomal Dominant Polycystic Kidney Disease (ADPKD)

Session Information

Category: Genetic Diseases of the Kidneys

  • 1101 Genetic Diseases of the Kidneys: Cystic

Authors

  • Lee, Edmund, Regulus Therapeutics Inc, San Diego, California, United States
  • Valencia, Tania M., Regulus Therapeutics Inc, San Diego, California, United States
  • Varrone, Francesca, Regulus Therapeutics Inc, San Diego, California, United States
  • Owen, Tate, Regulus Therapeutics Inc, San Diego, California, United States
  • Ramalingam, Harini, The University of Texas Southwestern Medical Center Department of Internal Medicine, Dallas, Texas, United States
  • Lakhia, Ronak, The University of Texas Southwestern Medical Center Department of Internal Medicine, Dallas, Texas, United States
  • Patel, Vishal, The University of Texas Southwestern Medical Center Department of Internal Medicine, Dallas, Texas, United States
  • Berman, Cindy L., Berman Consulting, Wayland, Massachusetts, United States
  • Garg, Rekha, PharmaDRS Consulting, San Diego, California, United States
  • Drygin, Denis, Regulus Therapeutics Inc, San Diego, California, United States
Background

ADPKD is mostly caused by PKD1 or PKD2 mutations, which reduce levels of their encoded proteins polycystin-1 (PC1) or polycystin-2 (PC2). Levels of PC1 and PC2 in urinary exosomes are lower in ADPKD patients than healthy volunteers and correlate inversely with disease severity in ADPKD patients. The miR-17 family of miRNAs is upregulated in human and mouse forms of ADPKD. Genetic deletion or pharmacological inhibition of miR-17 increases PC1 and PC2 levels and attenuate cyst growth in preclinical ADPKD models. Likewise, re-expression of PC1 and PC2 rapidly reverses disease progression in ADPKD mice. Importantly, treatment with the first-generation anti-miR-17 oligonucleotide RGLS4326 (1mg/kg) resulted in a statistically significant increase in urinary exosome PC1 and PC2 levels in patients with ADPKD. Together, these results suggested targeting miR-17 is an attractive therapeutic approach for treating ADPKD.

Methods

During development of RGLS4326, dose-limiting CNS toxicity was observed in mice and monkeys receiving high doses of RGLS4326 in nonclinical toxicity studies. Further investigations revealed that CNS toxicity was caused by direct off-target inhibition of the neuroreceptor, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA-R), by RGLS4326. Here, we discuss the discovery and characterization of the next-generation anti-miR-17 oligonucleotide RGLS8429 which has a similar efficacy profile as RGLS4326 without the affinity for AMPA-R.

Results

Like RGLS4326, RGLS8429 was designed to distribute preferentially to the kidney and inhibit miR-17 function. RGLS8429 showed similar potency profiles in inhibiting miR-17 function compared to RGLS4326 in vitro. RGLS8429 also showed similar pharmacodynamic and pharmacokinetic profiles after a single subcutaneous dose, and similar efficacy profile in ADPKD mouse models after repeat dosing, compared to RGLS4326 in vivo. As RGLS8429 did not cause off-target binding and inhibition of the AMPA-R, no CNS-related toxicity was observed in single- or repeat-dose toxicity studies in mice and monkeys.

Conclusion

A Phase 1b clinical trial evaluating RGLS8429 in ADPKD patients is planned for the second-half of 2022.

Funding

  • Commercial Support