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Abstract: PO1299

Sparsentan, the Dual Endothelin Angiotensin Receptor Antagonist (DEARA), Improves Kidney Function and Life Span and Protects Against Hearing Loss in Alport Mice with Developed Renal Structural Changes

Session Information

Category: Genetic Diseases of the Kidneys

  • 1002 Genetic Diseases of the Kidneys: Non-Cystic

Authors

  • Cosgrove, Dominic E., Boys Town National Research Hospital, Omaha, Nebraska, United States
  • Gratton, MichaelAnne, Washington University, St. Louis, Missouri, United States
  • Meehan, Daniel T., Boys Town National Research Hospital, Omaha, Nebraska, United States
  • Vosik, Denise, Boys Town National Research Hospital, Omaha, Nebraska, United States
  • Madison, Jacob D., Boys Town National Research Hospital, Omaha, Nebraska, United States
  • Delimont, Duane C., Boys Town National Research Hospital, Omaha, Nebraska, United States
  • Samuelson, Gina C., Boys Town National Research Hospital, Omaha, Nebraska, United States
  • Jarocki, Diana, Washington University, St. Louis, Missouri, United States
  • Komers, Radko, Travere Therapeutics Inc, San Diego, California, United States
  • Jenkinson, Celia P., Travere Therapeutics Inc, San Diego, California, United States
Background

In Alport syndrome (AS), endothelin type A receptor activation is an important mediator of renal and inner ear pathologies. Sparsentan (SP) administered to COL4A3 -/- mice (AS mice) in prevention mode delayed increases in proteinuria, renal structural changes and hearing loss (HL). Whether these effects translate into preservation of glomerular filtration rate (GFR), increased lifespan (LS) and protection from HL in mice where renal pathology has initiated is unknown.

Methods

Wild type (WT) and AS mice were gavaged daily with vehicle (WT-V or AS-V), 60 or 120 mg/kg SP (AS-SP60 or AS-SP120) starting at 4 weeks (W) of age or at 5, 6 or 7W. Baseline and 10W glomerulosclerosis (GS) were evaluated in kidney sections stained for fibronectin. GFR was measured using a transdermal device (Medibeacon) in mice treated from 4W. The auditory brainstem response (ABR) was used to assess hearing ability and sensitivity to noise at 8-8.75W in AS-V or AS-SP120 mice treated from 5W.

Results

SP begun at 4W abrogated the decline in GFR at 9W compared to AS-V mice (GFR µl/min mean ± SD; WT-V 159 ± 58 (n=6), AS-V 54.0 ± 30 (n=10), AS-SP60 148± 21 (n=6), AS-SP120 145 ± 42 (n=15); p<0.001 AS-V vs AS-SP60 or AS-SP120) and provided protection from GS in mice at 10W (P<0.01 AS-SP120 vs AS-V ). For LS studies GS (mean % sclerotic glomeruli) prior to treatment in AS mice was 0 at 4W, 5.2% at 5W, 23.3% at 6W and 47.0% at 7W and SP120 extended median LS (MLS) when dosing began even in 5, 6 or 7W mice with detectable GS (MLS days; AS-V 67.5, AS-SP120 4W start 118.0, AS-SP120 5W start 89.0, AS-SP120 6W start 88.0, AS-SP120 7W start 83.0). SP120 begun at 5W improved post noise thresholds with prevention of HL at 16 (P<0.05) and 24 Hz (P<0.01) (Mean ± SD dB SPL 16 Hz; WT-V 5 ± 6.1, AS-V 23 ± 9.7, AS-SP120 11 ± 4.2).

Conclusion

SP prevents the decline in GFR in AS mice, extends LS and prevents noise-induced HL even in mice with developed renal structural changes. If these results are translated successfully into the clinic, SP may offer a novel treatment approach for reducing both renal injury and protecting hearing in AS.

Funding

  • Commercial Support –