Abstract: TH-PO0367
Small Molecule Inhibition of TRPC5 Ameliorates Disease Progression in Murine Model of Alport Syndrome
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
- Keller, Keith H., Broad Institute, Cambridge, Massachusetts, United States
- Weishaupt, Luca Leon, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States
- Tseng, Wei Chou, Broad Institute, Cambridge, Massachusetts, United States
- Pablo, Juan Lorenzo B., Broad Institute, Cambridge, Massachusetts, United States
- Weins, Astrid, Brigham and Women's Hospital, Boston, Massachusetts, United States
- Greka, Anna, Broad Institute, Cambridge, Massachusetts, United States
Background
Alports syndrome (AS) is a hereditary kidney disorder due to mutations in type IV collagen (eg. COL4A5). Loss of COL4A5 leads to defects in collagen matrix formation resulting in a malformed GBM and eventually progressive glomerulonephritis. Affected males typically present in early childhood and progress to ESRD by their mid 20s to early 30s. Sustainable treatment for patients with AS remains elusive due to the nephrotoxic properties of current therapies (eg. cyclosporine). Recent studies have shown the efficacy of small molecule inhibition of TRPC5 (TRPC5i) in reducing urinary protein loss in murine models of focal segmental glomeulosclerosis (FSGS) through reinforcement of the actin cytoskeleton of the glomerular filtration barrier. Herein we tested the effectivness of this compound at reducing pathology in mice with a known genetic Col4a5 mutation.
Methods
4-week old male mice containing a nonsense mutation in Col4a5 (G5X) were treated daily by oral gavage with either 1mg/kg TRPC5i (n=6) or vehicle (n=6) for 14 weeks. Serum creatinine was measured at baseline, midpoint, and endpoint. Urinary albumin-to-creatinine ratio was measured bi-weekly. Kidney tissue was collected for gross histology and transmission electron microscopy (TEM). Kidney cryosections were stained for H&E and PAS followed by pathological evaluation. Glomerular alterations were evaluated in TEM images with basement membrane measurments performed both by harmonic mean and REMORA.
Results
AS mice treated with TRPC5i showed a marked reduction in proteinuria after 12 weeks compared to their vehicle treated littermates. Histologically, AS mice showed heterogenous pathology between animals, spanning from no noticable pathological changes to more severe chronic changes including FSGS, interstitial inflammation and tubular proteinacious casts. Despite this, the maximum pathological severity was higher in vehicle treated animals compared to TRPC5i treated animals. Lastly, GBM thinning, a hallmark of early AS, was significantly reduced in animals treated with TRPC5i. Collectively, these data suggest TRPC5i provides theraputic benefit to AS mice.
Conclusion
Since the TRPC5i used in this study has reached phase 2 clinical trials, our results are a promising proof of concept that motivates optimization of therapeutics focused on TRPC5 inhibition in AS.
Funding
- Private Foundation Support