Abstract: TH-PO0384
Optimization of the Adriamycin Mouse Model to Improve Translational Evaluation of Podocytopathy Therapies
Session Information
- Glomerular Diseases: Genetics to Therapeutics
October 22, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology
Authors
- Lincoln, Kathleen A., Boehringer Ingelheim Corp USA, Ridgefield, Connecticut, United States
- Robinson, Heather N., Boehringer Ingelheim Corp USA, Ridgefield, Connecticut, United States
- Rustam, Samir, Boehringer Ingelheim Corp USA, Ridgefield, Connecticut, United States
- Hamann, Stefan, Boehringer Ingelheim Corp USA, Ridgefield, Connecticut, United States
- Villalona, Jorge L., Boehringer Ingelheim Corp USA, Ridgefield, Connecticut, United States
- Love, Mark, Boehringer Ingelheim Corp USA, Ridgefield, Connecticut, United States
- Matera, Damian C., Boehringer Ingelheim Corp USA, Ridgefield, Connecticut, United States
- Mitola, Matthew, Boehringer Ingelheim Corp USA, Ridgefield, Connecticut, United States
- Hendricks, Lena, Boehringer Ingelheim Corp USA, Ridgefield, Connecticut, United States
- Spathis, Rita, Boehringer Ingelheim Corp USA, Ridgefield, Connecticut, United States
- Karlak, Aaron T., Boehringer Ingelheim Corp USA, Ridgefield, Connecticut, United States
- Fryer, Ryan M., Boehringer Ingelheim Corp USA, Ridgefield, Connecticut, United States
- Bruschetta, Giuseppe, Boehringer Ingelheim Corp USA, Ridgefield, Connecticut, United States
Background
CKD affects ~10% of the global population and frequently progresses to ESKD. Podocytopathies account for ~25–30% of ESKD cases and are characterized by podocyte injury, with urinary albumin/creatinine ratio (uACR) serving as a key translatable biomarker. Despite standard-of-care therapies including ACE inhibitors, Angiotensin receptor blockers (ARB)s, and endothelin receptor antagonists (ERA)s, there remains a significant unmet need for disease-modifying treatments. Pre-clinically, translation has also been limited by high variability and, at times, poor reproducibility of the Adriamycin (ADR) mouse model for robust evaluation of novel therapies.
Methods
We optimized the ADR model by evaluating administration route (tail vein vs. jugular vein), strain susceptibility (Balb/c, 129S1, C57BL/6J), and treatment dosing strategy over 2 weeks post-induction. Therapeutic response to enalapril and ERA+ARB was assessed up to 6 weeks. Disease progression was measured by longitudinal uACR, histopathology [glomerulosclerosis (GS), tubulointerstitial fibrosis (TIF)], and high-plex COMET immunofluorescence imaging to assess podocyte injury, inflammation, mesangial activation, and ECM remodeling.
Results
Jugular vein administration of ADR (10 mg/kg) in 129S1 mice eliminated tail vein–associated pathology and produced a consistent disease induction. At 2 weeks, ADR increased uACR concomitant with GS (44% above control) and a 60% reduction in nephrin expression; additionally, COMET analysis demonstrated expansion of immune cell populations, mesangial activation, and ECM-producing cells. Elevations in uACR were sustained throughout the 6 weeks. Therapeutic treatment with enalapril or ERA+ARB reduced uACR by at least half (up to 68% reduction). Moreover, both treatments attenuated GS, while ERA+ARB also reduced TIF (–54%) and biomarkers of podocyte injury.
Conclusion
A dose- and route-optimized ADR model in 129S1 mice demonstrates improved reproducibility, reduced procedural variability, and clear sensitivity to standard-of-care therapies. The model provides a robust and translationally relevant platform for evaluating novel therapies targeting podocyte injury and progressive CKD.
Funding
- Commercial Support – Boehringer Ingelheim