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Abstract: SA-PO788

Small Molecule Inhibition of APOL1 Reverses Albuminuria in a Chronic Mouse Model of APOL1-Mediated Kidney Disease

Session Information

Category: Genetic Diseases of the Kidneys

  • 1202 Genetic Diseases of the Kidneys: Non-Cystic

Authors

  • Assimon, Victoria, Maze Therapeutics Inc, South San Francisco, California, United States
  • Bronner, Sarah, Maze Therapeutics Inc, South San Francisco, California, United States
  • Yu, Cecile, Maze Therapeutics Inc, South San Francisco, California, United States
  • Chan, Helen, Maze Therapeutics Inc, South San Francisco, California, United States
  • Crasta, Sheela, Maze Therapeutics Inc, South San Francisco, California, United States
  • Lee, Patrick S., Maze Therapeutics Inc, South San Francisco, California, United States
  • Lin, Baiwei, Maze Therapeutics Inc, South San Francisco, California, United States
  • Luo, Yunqi, Maze Therapeutics Inc, South San Francisco, California, United States
  • Octaviani, Angela, Maze Therapeutics Inc, South San Francisco, California, United States
  • Reid, Adam, Maze Therapeutics Inc, South San Francisco, California, United States
  • Sanman, Laura, Maze Therapeutics Inc, South San Francisco, California, United States
  • Shi, Licheng, Maze Therapeutics Inc, South San Francisco, California, United States
  • Situ, Eva, Maze Therapeutics Inc, South San Francisco, California, United States
  • Tep, Sam, Maze Therapeutics Inc, South San Francisco, California, United States
  • Zhang, Birong, Maze Therapeutics Inc, South San Francisco, California, United States
  • Beattie, David T., Maze Therapeutics Inc, South San Francisco, California, United States
  • Sinz, Christopher, Maze Therapeutics Inc, South San Francisco, California, United States
  • Hoek, Maarten, Maze Therapeutics Inc, South San Francisco, California, United States
  • Bernstein, Harold S., Maze Therapeutics Inc, South San Francisco, California, United States
  • Morgans, David John, Maze Therapeutics Inc, South San Francisco, California, United States
  • Green, Eric, Maze Therapeutics Inc, South San Francisco, California, United States
Background

Two coding variants in the APOL1 gene (G1 and G2) confer a greater risk for progressive, proteinuric kidney disease in individuals of African ancestry. Available therapies do not address the causal genetic driver of disease, highlighting the need for novel efficacious APOL1-targeted treatments. We have previously shown that pharmacologic inhibition of APOL1 pore function ameliorates albuminuria in an acute mouse model of APOL1-mediated kidney disease (AMKD). Here we describe the development of a chronic mouse model of AMKD with robust albuminuria and glomerulosclerosis and demonstrate that inhibition of APOL1 with a small molecule attenuates these features of AMKD.

Methods

A novel model, heterozygous for the APOL1 G1/G2 variants, was developed for these studies in addition to the homozygous APOL1 G2 mouse model previously described. Continuous increased APOL1 expression was achieved by infecting mice with an adeno-associated virus (AAV) engineered to express interferon-γ (IFN-γ). These mouse models were used to assess the effect of APOL1 small molecule inhibition on glomerular injury and urinary albumin-to-creatinine ratios (UACR).

Results

Administration of AAV-IFN-γ in APOL1 transgenic mice increased interferon levels and signaling after virus injection and led to sustained APOL1 induction, elevated UACR, and glomerulosclerosis on both genetic backgrounds. Oral administration of an APOL1 inhibitor robustly attenuated chronic IFN-γ–induced albuminuria in APOL1 transgenic mice.

Conclusion

Small molecule inhibition of APOL1 attenuates albuminuria in a chronic mouse model of AMKD. These findings support continued development of precision medicines for patients with AMKD.

Funding

  • Commercial Support – Maze Therapeutics