Abstract: TH-PO481
The NOX Inhibitor Setanaxib Combined with Ramipril Reduces Glomerular Function Decline and Fibrosis in a Mouse Model of Alport Syndrome
Session Information
- Genetic Diseases: Glomerulopathies - I
November 02, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1202 Genetic Diseases of the Kidneys: Non-Cystic
Authors
- Christophe, Thierry, Calliditas Therapeutics AB, Stockholm, Stockholm County, Sweden
- Fresquet, Maryline, Wellcome Centre for Cell-Matrix Research, Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology Medicine and Health, The University of Manchester, Manchester, United Kingdom
- Morais, Mychel R P T, Wellcome Centre for Cell-Matrix Research, Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology Medicine and Health, The University of Manchester, Manchester, United Kingdom
- Lawless, Craig, Wellcome Centre for Cell-Matrix Research, Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology Medicine and Health, The University of Manchester, Manchester, United Kingdom
- Lennon, Rachel, Wellcome Centre for Cell-Matrix Research, Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology Medicine and Health, The University of Manchester, Manchester, United Kingdom
Background
Alport syndrome is a rare genetic disorder, which presents in childhood or adolescence. It is caused by genetic variants affecting type IV collagen, leading to progressive kidney damage. Setanaxib, an NADPH oxidase (NOX) inhibitor, has been shown in preclinical models to reduce inflammation and fibrosis – mechanisms known to play a role in Alport syndrome disease progression. In this study, we assessed the therapeutic potential of setanaxib in a mouse model of Alport syndrome.
Methods
Four-week-old Col4a3 -/- mice on 129/SvJ background (n=10 per group) were given 10 mg/kg ramipril (an ACE inhibitor [ACEi]) in drinking water, 60 mg/kg setanaxib once daily by gavage, setanaxib and ramipril combined, or vehicle, over 4 weeks. At the end of the study, kidneys were analyzed by imaging and proteomics.
Results
Urinary albumin levels and albumin/creatinine ratio were reduced at 6 and 8 weeks of age in mice receiving ramipril alone, with a further reduction seen in mice receiving setanaxib and ramipril combined (Fig. 1A,B). Histologic analysis indicated that setanaxib and ramipril combined also significantly decreased glomerular sclerosis (scored by a pathologist) and overall fibrosis (Fig. 1C-E). Proteomic and in silico analyses also reported increased detection of glomerular basement membrane and collagen proteins with setanaxib and ramipril combined.
Conclusion
These results indicate that setanaxib, when combined with the standard of care ACEi, induced mechanisms that reduced the decline in glomerular function and fibrosis in a well-established mouse model of Alport syndrome.
Funding
- Commercial Support – Calliditas Therapeutics