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Abstract: FR-PO344

Knock-Down of Uromodulin Using Antisense Oligonucleotides as a Potential Treatment for Autosomal Dominant Tubulointerstitial Kidney Disease

Session Information

Category: Genetic Diseases of the Kidneys

  • 1102 Genetic Diseases of the Kidneys: Non-Cystic

Authors

  • Morgan, Kathy Ye, Sarepta Therapeutics Inc, Cambridge, Massachusetts, United States
  • Jungels, Nino, Sarepta Therapeutics Inc, Cambridge, Massachusetts, United States
  • Oliver, Ryan A., Sarepta Therapeutics Inc, Cambridge, Massachusetts, United States
  • Jinadasa, Tushare, Sarepta Therapeutics Inc, Cambridge, Massachusetts, United States
  • Adhikari, Kailash, Sarepta Therapeutics Inc, Cambridge, Massachusetts, United States
  • Kern, Nicholas L., Sarepta Therapeutics Inc, Cambridge, Massachusetts, United States
  • Sohail, Saad, Sarepta Therapeutics Inc, Cambridge, Massachusetts, United States
  • Garcia, Stephanie, Sarepta Therapeutics Inc, Cambridge, Massachusetts, United States
  • Malmberg, Annika, Sarepta Therapeutics Inc, Cambridge, Massachusetts, United States
  • Kim, Kevin, Sarepta Therapeutics Inc, Cambridge, Massachusetts, United States
Background

Autosomal Dominant Tubulointerstitial Kidney Disease-Uromodulin (ADTKD-UMOD) is a genetic disease caused by mutations in the uromodulin (UMOD) or Tamm-Horsfall protein. The misfolded UMOD prevents the secretion of the protein and causes intracellular UMOD to aggregate and accumulate inside the loop of Henle and distal convoluted tubule. This aggregation leads to progressive and irreversible chronic kidney disease. We hypothesized that peptide-conjugated phosphorodiamidate morpholino oligonucleotides (PPMOs) can knock down UMOD expression, which can potentially reduce the disease-causing UMOD aggregation inside the cells.

Methods

A library of PPMOs was designed to bind to the complementary sequences of the mouse Umod gene and induce nonsense-mediated decay. These PPMOs were screened in mIMCD-3 cells, which express endogenous Umod, to find the most efficacious sequence. The sequence that caused the largest Umod knockdown was then further characterized in vitro and in vivo.

Results

After screening the library of PPMOs, PPMOs that exhibited knockdown of Umod expression were further characterized and demonstrated robust knockdown of Umod expression in a dose-dependent manner in mIMCD-3 cells. In the high dose group, up to 85% knockdown of Umod expression was observed. PPMO was then dosed in wild-type mice where up to 70% knockdown of Umod was observed.

Conclusion

PPMOs to knockdown Umod and have shown their efficacy both in vitro and in vivo. These findings demonstrate that PPMOs have the potential to preserve renal function in patients with ADTKD.

Funding

  • Commercial Support