Abstract: FR-PO0104
Therapeutic Efficacy of GP-051 Monotherapy and Combination Therapy with ARBs in a Severe Alport Syndrome Mouse Model
Session Information
- Hereditary Glomerular and Tubulointerstitial Kidney Diseases
October 23, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1202 Genetic Diseases of the Kidneys: Non-Cystic (Complex and Non-Cystic Monogenic)
Authors
- Tsuhako, Haruki, Kumamoto University Graduate School of Pharmaceutical Sciences Department of Molecular Medicine, Kumamoto, Japan
- Mizumoto, Keito, Kumamoto University Graduate School of Pharmaceutical Sciences Department of Molecular Medicine, Kumamoto, Japan
- Horizono, Jun, Kumamoto University Graduate School of Pharmaceutical Sciences Department of Molecular Medicine, Kumamoto, Japan
- Suico, Mary Ann, Kumamoto University Graduate School of Pharmaceutical Sciences Department of Molecular Medicine, Kumamoto, Japan
- Shuto, Tsuyoshi, Kumamoto University Graduate School of Pharmaceutical Sciences Department of Molecular Medicine, Kumamoto, Japan
- Kai, Hirofumi, Kumamoto University Graduate School of Pharmaceutical Sciences Department of Molecular Medicine, Kumamoto, Japan
Background
Renin-angiotensin-aldosterone system (RAAS) inhibitors are widely used to suppress progressive proteinuria in patients with Alport syndrome (AS). We previously showed that GP-051, a Keap1-Nrf2 protein-protein interaction (PPI) inhibitor, combined with losartan exerted renoprotective effects and prolonged survival in the C57BL/6J-background Col4a5 G5X AS mouse model. In this study, we evaluated the therapeutic efficacy of GP-051 combined with angiotensin receptor blockers (ARBs) in the more commonly used 129X1/SvJ-background Col4a3-/- AS mouse model.
Methods
129X1/SvJ Col4a3-/- mice were treated with GP-051 (1 or 3 mg/kg/day, p.o.) and either losartan (125 μg/mL, ad libitum) or olmesartan (50 μg/mL, ad libitum) as monotherapy or combination therapy.
Results
GP-051 (3 mg/kg), losartan, and olmesartan monotherapy increased median survival by 10.0%, 6.5%, and 33.9%, respectively, versus vehicle-treated controls. The combination of olmesartan and GP-051 (3 mg/kg) produced the greatest benefit, extending mean survival by 70.2%. Combination treatment with GP-051 (3 mg/kg) and either losartan or olmesartan further prolonged survival compared with the respective ARB monotherapy, indicating an additive survival benefit. Urinalysis showed that GP-051 monotherapy (1 or 3 mg/kg) reducedproteinuria at 8 weeks of age, even in the rapidly progressive 129X1/SvJ-background AS model. Combination treatment with losartan and GP-051 (either 1 or 3 mg/kg) further reduced proteinuria compared with losartan monotherapy, whereas addition of GP-051 to olmesartandid not further reduce proteinuria. These findings suggest that mechanisms beyond antiproteinuric effects may contribute to the marked survival benefit with olmesartan plus GP-051.
Conclusion
GP-051 exerted significant renoprotective effects in a severe AS mouse model. Combination treatment with GP-051 and ARBs may represent a promising therapeutic strategy for AS and other chronic kidney diseases.
Funding
- Government Support – Non-U.S.