Abstract: FR-PO0691
Therapeutic Targeting of Ire1alpha Endoribonuclease Domain Ameliorates ADPKD in Orthologous Mouse Models
Session Information
- Cystic Kidney Diseases: Basic and Translational Research
November 07, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1201 Genetic Diseases of the Kidneys: Monogenic Kidney Diseases
Authors
- Bhardwaj, Rishi, Yale School of Medicine, New Haven, Connecticut, United States
- Hasan, Fatema, Yale School of Medicine, New Haven, Connecticut, United States
- Volpe, Isabel, Yale School of Medicine, New Haven, Connecticut, United States
- Yilmaz, Duygu Elif, Charite - Universitatsmedizin Berlin, Berlin, BE, Germany
- Pioppini, Carlotta, Charite - Universitatsmedizin Berlin, Berlin, BE, Germany
- Rehman, Michael, Yale School of Medicine, New Haven, Connecticut, United States
- Cai, Yiqiang, Yale School of Medicine, New Haven, Connecticut, United States
- Somlo, Stefan, Yale School of Medicine, New Haven, Connecticut, United States
- Krappitz, Matteus, Yale School of Medicine, New Haven, Connecticut, United States
- Fedeles, Sorin V., Yale School of Medicine, New Haven, Connecticut, United States
Background
The Ire1α-XBP1 pathway is the most conserved branch of the unfolded protein response (UPR) from yeast to mammals. The endoribonuclease domain of Ire1α excises an intron from the XBP1 mRNA, to form the full-length transcription factor, XBP1s. We previously showed that genetic inactivation of either XBP1 or the Ire1α endoribonuclease domain significantly reduced cystic disease progression in Pkd1-dependent ADPKD mouse models by selectively inducing apoptosis in cystic cells (abstract TH-OR63). Here, we evaluated the therapeutic efficacy of chemically inhibiting the Ire1α endoribonuclease domain in adult orthologous mouse models of ADPKD, including Pkd1-deficient and Pkd1 hypomorphic (R2216W) mice.
Methods
We generated Pkd1flox/flox or hypomorphic Pkd1R2216W/flox mice under the control of Pax8-rtTA;TetO-Cre. aWe assessed the impact of chemical inhibition of the Ire1α endoribonuclease domain on disease progression via toyocamycin (a potent Ire1alpha endoribonuclease domain inhibitor previously used in a Phase 1 trial). Outcomes included histological and functional parameters.
Results
Chemical inhibition of the Ire1α endoribonuclease domain led to the almost complete absence of spliced XBP1 protein expression following ER stress induction in mice. We followed this with in vivo therapeutic experiments where mice received intraperitoneal injections of toyocamycin biweekly at a dose of 0.5 mg/kg until 18 weeks of age. Treated mice displayed a very significant improvement in kidney-to-body weight ratios (KW/BW) compared to untreated knockout controls: Pkd1 LOF treated mice had a 46.31% reduction, 8.036±1.311 vs 14.970±1.041; ***p=0.0003 and Pkd1-R2216W hypomorphic treated mice a 35% reduction, 5.495±0.675 vs 8.435±0.814; **p=0.009). Additionally, improved renal function parameters (serum creatinine) in the treated mice correlated positively with the observed KW/BW improvements i.e. Pkd1-LOF treated mice showed a 40.9% reduction, 0.39±0.11 vs 0.66±0.06; *p=0.038 and Pkd1-R2216W a 46.02% reduction, 0.137±0.014 vs 0.255±0.026; ***p=0.0005).
Conclusion
Our findings highlight the therapeutic potential of chemically inhibiting the Ire1α endoribonuclease domain as a novel approach to mitigate ADPKD progression in an allele independent fashion.
Funding
- Other U.S. Government Support