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Abstract: TH-PO442

APOL1 Inhibitors Reverse Established Proteinuria in an APOL1-Mediated Kidney Disease Mouse Model

Session Information

Category: Glomerular Diseases

  • 1302 Glomerular Diseases: Immunology and Inflammation

Authors

  • Blasio, Angelo, Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, United States
  • Sullivan, Kelly E., Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, United States
  • Mann, James J., Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, United States
  • Wang, Guanyu, Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, United States
  • Kumar, Shyamesh, Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, United States
  • Bright, Franklin, Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, United States
  • Bouillez, Audrey, Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, United States
  • Daniel, Kevin, Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, United States
  • Nanthakumar, Suganthini, Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, United States
  • Rosario, Aldo A., Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, United States
  • Aragon Mejia, Monica A., Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, United States
  • Heighton, Thomas F., Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, United States
  • Nanou, Evanthia, Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, United States
  • Proctor, Jennifer, Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, United States
  • Furey, Brinley, Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, United States
  • Fortier, Anne, Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, United States
  • Senter, Timothy J., Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, United States
  • Dakin, Leslie, Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, United States
  • Zimmerman, Brandon, Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, United States
Background

APOL1-mediated kidney disease (AMKD) is a progressive, proteinuric nephropathy caused by gain-of-function variants (G1 or G2) in APOL1. There are currently no treatments addressing the underlying cause of AMKD. Our previous data showed that novel small molecule APOL1 inhibitors prevent proteinuria prophylactically in a model of transient AMKD. In a Ph2a trial, the APOL1 small molecule inhibitor inaxaplin (IXP; VX-147) significantly reduced proteinuria in participants with 2 APOL1 variants, proteinuria, and FSGS. Here we demonstrate that another small molecule APOL1 inhibitor with similar potency to IXP intervenes therapeutically in a novel mouse model of AMKD.

Methods

To develop a mouse model of AMKD, we utilized transgenic APOL1 mice homozygous for the APOL1 G2 mutation (G2Hom). Osmotic pumps were implanted into G2Hom and wild-type FVB (control) mice to deliver a continuous infusion of interferon g (IFNg) or saline. G2Hom mice were treated with a small molecule APOL1 inhibitor or vehicle 5 days after IFNg or saline infusion was initiated. Proteinuria and body weight were assessed daily. Kidney sections were evaluated histologically and quantitative image analysis assessed APOL1 expression and nephrin levels in glomeruli.

Results

Administration of IFNg in G2Hom mice led to a dramatic increase in proteinuria within 5 days and significant loss in body weight. Proteinuria remained stable and elevated for 2 weeks. Treatment with APOL1 inhibitor significantly reduced proteinuria, returning it to baseline within a week, and restored body weight. Modest histological changes and nephrin loss in glomeruli were observed in the vehicle group and absent in the APOL1 inhibitor treatment group. Control mice injected with IFNg and G2Hom mice injected with saline did not develop proteinuria or have signs of kidney disease.

Conclusion

We demonstrated that APOL1 inhibitors reverse proteinuria after APOL1-mediated damage is initiated and protect against disease progression during constant inflammatory challenge. These data support the results of the Ph2a trial with IXP.