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Abstract: PO1403

Effects of ANG-3070 in a Mouse Model of Alport Syndrome

Session Information

Category: Glomerular Diseases

  • 1201 Glomerular Diseases: Fibrosis and Extracellular Matrix

Authors

  • Paka, Latha, Angion Biomedica Corp, Uniondale, New York, United States
  • Prakash, Natalia, Angion Biomedica Corp, Uniondale, New York, United States
  • Jiang, Kai, Angion Biomedica Corp, Uniondale, New York, United States
  • Narayan, Prakash, Angion Biomedica Corp, Uniondale, New York, United States
  • Goldberg, Itzhak D., Angion Biomedica Corp, Uniondale, New York, United States
Background

Alport syndrome (AS) is a hereditary kidney disease that presents in childhood and progresses to end stage kidney disease (ESKD) in adolescence. There are no approved therapies. AS is caused by mutations in type IV collagen genes Col4a3, a4 or a5, that result in reduced structural integrity of the glomerular basement membrane, triggering activation of fibrogenic cytokines, including platelet derived growth factor (PDGF) and transforming growth factor beta (TGFβ1) causing proteinuric disease and fibrosis. We hypothesize that an antifibrotic therapy may decrease proteinuria-induced fibrosis, and evaluated ANG-3070, a novel tyrosine kinase inhibitor, in a Col4a3 knockout mouse model of AS.

Methods

After confirming the Col4a3 mutation by genotyping, 4-week-old male and female Alport mice were randomized to Vehicle (oral, twice-daily) or ANG-3070 (oral, 25 mg/kg, twice-daily) for 5 weeks (n=12/ group). Age-matched, wild-type mice were included (n=9) as a control. Animals were sacrificed after 5 weeks of treatment, after collecting spot urines to measure protein to creatinine ratio (PCR). Renal tissue was analyzed for hydroxyproline (HYP) content, by Western blot for tissue fibrotic markers, and for histopathology using hematoxylin-eosin (H&E) staining for renal damage score and picrosirius red (PSR) staining for fibrosis. All histological analyses were performed blindly by two independent observers using a 0-4 scale (0 being normal, 4 ≥ 75% injured or stained).

Results

ANG-3070 treatment reduced mortality (survivors; Vehicle: 8/12 vs ANG-3070: 12/12 ). In surviving mice, proteinuria was reduced (mg/ml; Vehicle 6.2 vs ANG-3070 3.1; p<0.05) along with PCR (mg/mg; Vehicle 11.1 vs ANG-3070 5.5; p<0.05). There was a reduction in renal damage (Vehicle: 2.6 vs ANG-3070: 1.2; p = 0.002) along with renal fibrosis (Vehicle 2.4 vs ANG-3070 1.2; p=0.001). When kidney lysates were evaluated, HYP content was reduced (μg/kidney; Vehicle, 132 vs ANG-3070, 57; p <0.002) along with fibrotic markers of collagen-1, TGFβ1, and α smooth muscle actin (αSMA) compared to Vehicle-treated Alport mice (p<0.05). Additionally, PDGFR expression was reduced (p<0.05).

Conclusion

Treatment with a novel tyrosine kinase inhibitor, ANG-3070, was efficacious in AS mice compared to Vehicle. ANG-3070 may represent a novel therapeutic for AS.

Funding

  • Commercial Support