Abstract: SA-PO0204
Integrating Standard of Care into Rodent CKD Models for Discovering Synergistic Therapies Through High-Throughput In Vivo Functional Genomic Screens
Session Information
- CKD: Mechanisms of Injury and Fibrosis - 3
October 24, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2203 CKD (Non-Dialysis): Mechanisms
Authors
- Pharaoh, Gavin, Gordian Biotechnology Inc, South San Francisco, California, United States
- Sontake, Vishwaraj, Gordian Biotechnology Inc, South San Francisco, California, United States
- Wang, Shengping, Gordian Biotechnology Inc, South San Francisco, California, United States
- Le, Carmen, Gordian Biotechnology Inc, South San Francisco, California, United States
- Miyazaki, Hikaru, Gordian Biotechnology Inc, South San Francisco, California, United States
- Nonora, Jesi Rith, Gordian Biotechnology Inc, South San Francisco, California, United States
- Ruiz, Sophia, Gordian Biotechnology Inc, South San Francisco, California, United States
- Fuentes, Daniel R., Gordian Biotechnology Inc, South San Francisco, California, United States
- Garcia, Diego, Gordian Biotechnology Inc, South San Francisco, California, United States
- Fung, Lianna, Gordian Biotechnology Inc, South San Francisco, California, United States
- Hayward, Samuel Bryant, Gordian Biotechnology Inc, South San Francisco, California, United States
- Jensen, Martin, Gordian Biotechnology Inc, South San Francisco, California, United States
Background
Expanding the therapeutic space for chronic kidney disease (CKD) requires capturing dysregulated multicellular circuits using in vivo models treated with standard of care (SoC) therapies, coupled with high-throughput functional genomics. To bridge this translational gap, we optimized two CKD models (adenine diet and ZSF1 obese rat) incorporating SoC regimens specifically designed for in vivo functional genomics.
Methods
10-wk-old male C57BL/6J mice received control or 0.2% adenine diet for 3 wks followed by chow reversal. To optimize therapeutic timing, empagliflozin (empa; 30 mpk) began on day 0, 7, or 14 of adenine feeding. 10-wk-old male ZSF1 obese rats underwent uninephrectomy (1K) and compared to WKY and ZSF1 lean and obese (2K) controls. Three months post-surgery, dual SoC (empa 30 mpk; lisinopril 10 mpk) was initiated. Progression was monitored via transdermal GFR (tGFR), serum cystatin C, and UACR. For perturbation delivery, barcoded AAV constructs were coupled with scRNA-seq to identify cell type specificity.
Results
Adenine diet induced rapid body weight and tGFR (~80%) decline, with mild UACR elevation. Prophylactic empa (day 0) partially protected weight and tGFR, whereas therapeutic dosing (days 7, 14) did not. Proportion of fibrotic and inflammatory fibroblasts, pericytes, and maladaptive repair PTECs increased dramatically. Further, our scRNA-seq data identified AAV serotype and promoter specific to these pathogenic cell types.
In ZSF1-obese rats, 1K obese animals showed elevated cystatin C and reduced tGFR compared to 2K obese and lean. UACR was highly elevated in both 1K and 2K obese relative to WKY/lean controls. Empa increased urinary glucose, and lisinopril reduced blood pressure. Dual therapy significantly reduced UACR and induced an initial tGFR decline, replicating the hemodynamic GFR dip observed in CKD patients.
Conclusion
SoC provided partial renoprotection in both adenine and ZSF1 CKD models, leaving a therapeutic window to evaluate novel interventions. Notably, the ZSF1 1K model successfully mimics progressive diabetic kidney disease with clinically relevant comorbidities and hemodynamics. Together these SoC-integrated models coupled with AAV based perturbation delivery provide a robust foundation for high-throughput in vivo screening to discover therapies that act synergistically with approved therapies.
Funding
- Commercial Support – Gordian Biotechnology