Kidney Week

Abstract: TH-OR063

Antisense Oligotherapy Against Metabolic Sensor O-GlcNAc Transferase Mitigates PKD in Mice

Session Information

• Genetic Diseases with a Focus on ADPKD Mechanisms, Models, and Medicines
  October 22, 2026 | Location: Mile High Ballroom 4D, Convention Center
  Abstract Time: 05:50 PM - 06:00 PM

Category: Genetic Diseases of the Kidneys

• 1201 Genetic Diseases of the Kidneys: Cystic (Monogenic)

Authors

• Ranganathan, Chadhve, The University of Kansas Medical Center, Kansas City, Kansas, United States

Chadhve Ranganathan

• Kavanaugh, Matthew A., The University of Kansas Medical Center, Kansas City, Kansas, United States

Matthew A. Kavanaugh

• Parnell, Stephen C., The University of Kansas Medical Center, Kansas City, Kansas, United States

Stephen C. Parnell, PhD

• Slawson, Chad, The University of Kansas Medical Center, Kansas City, Kansas, United States

Chad Slawson, PhD

• Tran, Pamela Vivian, The University of Kansas Medical Center, Kansas City, Kansas, United States

Pamela Vivian Tran, PhD

Background

Autosomal Dominant Polycystic Kidney Disease (ADPKD) causes the progressive growth of kidney cysts leading to renal failure typically in the 6^th decade of life. Tolvaptan, the only FDA-approved therapy, has variable effectiveness and aquaretic side effects. As such, the need to develop novel therapies continues.

Altered cellular metabolism is an important component of ADPKD pathogenesis. We have reported that the metabolically regulated post-translational modification, O-GlcNAcylation, is increased in ADPKD kidneys, and that deletion of O-GlcNAc transferase (Ogt) in ADPKD mouse models markedly attenuates disease severity and extends survival >17-fold. Untargeted metabolomics revealed that Ogt ties metabolism to both intracellular and extracellular mechanisms of cyst formation, indicating Ogt is a critical regulatory node. To target Ogt pharmacologically, we sought to determine whether administration of an Ogt antisense oligonucleotide (ASO) is therapeutic in an orthologous ADPKD mouse model.

Methods

We examined efficacy of five Ogt ASOs to knock down Ogt expression in NIH/3T3 cells. We administered the most effective ASO to adult Pkd2 conditional knockout (cko); Pax8rtTA;LC1-Cre mice. Pkd2 was deleted by administering doxycycline in the drinking water from 4 to 6 weeks of age. Ogt ASO was injected intraperitoneally (50mg/kg) into Pkd2 cko mice weekly from 4 weeks to 4 months of age. At 4 months of age, mice were dissected and kidneys were assessed via histology, immunostaining, Western blot, and blood urea nitrogen (BUN) levels.

Results

Of five Ogt ASOs examined in NIH/3T3 cells, ASO3 was the most effective, knocking down Ogt expression by >80%. Adminstration of Ogt ASO3 to Pkd2 cko mice reduced O-GlcNAc levels in the kidney and markedly reduced renal cysts and kidney weight/body weight ratios, without altering body weight. Vehicle (PBS) versus Ogt ASO3 resulted in body weights of 25.7g ± 0.78 and 27.9g ± 0.07 (mean ± sd), respectively, and in total kidney weights of 3.2g ± 0.67 and 0.88g ± 0.006, respectively. Ogt ASO3 reduced kidney inflammation and fibrosis. Ogt ASO3 also reduced BUN levels, indicating preserved kidney function.

Conclusion

Ogt ASO3 administration markedly attenuated ADPKD severity, suggesting strong therapeutic potential. To our knowledge, this is the first demonstration of an Ogt ASO therapeutic for any disorder.

Funding

• Other NIH Support