Abstract: PO1965
Urinary Rac1, a Novel Predictive Biomarker, Is Elevated in FSGS and Diabetic Nephropathy Patients and Reduced by TRPC5 Inhibition with GFB-887 in a Rat FSGS Model
Session Information
- Podocyte Biology
October 22, 2020 | Location: On-Demand
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1204 Podocyte Biology
Authors
- Dagon, Yossi, Goldfinch Bio Inc, Cambridge, Massachusetts, United States
- Raghu, Hari, Goldfinch Bio Inc, Cambridge, Massachusetts, United States
- Ge, Tingting, Goldfinch Bio Inc, Cambridge, Massachusetts, United States
- Walsh, Liron, Goldfinch Bio Inc, Cambridge, Massachusetts, United States
- Reilly, John F., Goldfinch Bio Inc, Cambridge, Massachusetts, United States
Background
Activation of Ras-related C3 botulinum toxin substrate 1 (Rac1) plays a key role in podocyte injury and dysfunction in focal segmental glomerular sclerosis (FSGS) and diabetic nephropathy (DN). In diseased podocytes, Rac1 activation is mediated by calcium influx through the transient receptor potential canonical 5 (TRPC5) ion channel. GFB-887 is a sub-type selective, small molecule inhibitor of TRPC5 that reduces albuminuria in deoxycorticosterone acetate (DOCA)-salt and ZDSD rat models of FSGS and DN, respectively. Here, we aimed to develop a urinary biomarker to assess podocyte Rac1 activity in kidney disease and in response to GFB-887 treatment.
Methods
Using a sandwich ELISA, we measured Rac1 concentrations in supernatants from cultured human iPSC-derived podocytes, in urine from DOCA-salt rats following treatment with GFB-887, and in urine from healthy volunteers, FSGS, DN and Alport patients.
Results
Rac1 was detected in extracellular vesicles (EV) isolated from podocyte culture supernatant and rat and human urine. GFB-887 treatment lowered urinary Rac1 concentrations in normal and DOCA-salt rats, and the decreased Rac1 was associated with decreased albuminuria in the DOCA-salt rats. Urinary Rac1 concentrations were markedly elevated in FSGS and DN but not in Alport patients.
Conclusion
The TRPC5 inhibitor, GFB-887, targets the TRPC5-Rac1 pathway and suppresses urinary Rac1 associated with its therapeutic action in a rat model of FSGS. Urinary Rac1 concentrations are markedly higher in FSGS and DN compared to healthy subjects, but not elevated in Alport. GFB-887 is efficacious in rodent models of FSGS and DN, but not of Alport, suggesting that elevated urinary Rac1 is predictive of response. Together, these data support the potential for clinical utilization of urinary Rac1 as a pharmacodynamic and predictive biomarker for GFB-887 treatment in FSGS and DN. GFB-887 is currently being studied in TRACTION™, a Phase 2 clinical trial in FSGS and DN in which baseline and on-treatment urinary Rac1 measurements will support further development of the biomarker.
Funding
- Commercial Support –