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Abstract: FR-PO318

MZ-301 Is a Small Molecule Inhibitor of APOL1 Pore Function That Attenuates Albuminuria in a Mouse Model of APOL1-Mediated Kidney Disease

Session Information

Category: Genetic Diseases of the Kidneys

  • 1102 Genetic Diseases of the Kidneys: Non-Cystic

Authors

  • Assimon, Victoria, Maze Therapeutics, South San Francisco, California, United States
  • Bronner, Sarah, Maze Therapeutics, South San Francisco, California, United States
  • Yu, Cecile, Maze Therapeutics, South San Francisco, California, United States
  • Zha, Weibin, Maze Therapeutics, South San Francisco, California, United States
  • Hoek, Maarten, Maze Therapeutics, South San Francisco, California, United States
  • Sinz, Christopher, Maze Therapeutics, South San Francisco, California, United States
  • Green, Eric, Maze Therapeutics, South San Francisco, California, United States
  • Morgans, David John, Maze Therapeutics, South San Francisco, California, United States
Background

APOL1 genetic variants (G1 and G2) increase risk for a spectrum of progressive kidney diseases in people of African ancestry. To date, no APOL1-targeted therapies are available that address the underlying genetic driver of disease. Here we describe the in vitro and in vivo activity of MZ-301, a small molecule APOL1 pore blocker that reduces APOL1-driven toxicity in multiple cell systems and attenuates albuminuria in a mouse model of APOL1-mediated kidney disease.

Methods

A parasite viability assay was used to quantify the ability of recombinant APOL1 protein to lyse trypanosomes in the presence and absence of MZ-301. MZ-301 inhibition of APOL1 pore function was determined in HEK293 cells overexpressing APOL1. Additionally, MZ-301 inhibition of APOL1 cytotoxicity was assessed in HEK293 cells and immortalized podocytes overexpressing APOL1. Finally, transgenic mice homozygous for the APOL1 G2 (G2HOM) variant were administered an IFN-γ challenge to elevate APOL1 levels and induce albuminuria. This mouse model was used to assess the effect of MZ-301 on urine albumin-to-creatinine ratios.

Results

MZ-301 potently blocked the lytic activity of APOL1, preventing APOL1-mediated killing of trypanosomes. This compound also inhibited APOL1-dependent cytotoxicity in HEK293 cells and immortalized podocytes and reduced APOL1 ion conductance in APOL1-overexpressing HEK293 cells. Cellular effects were consistent across G1 and G2 variants. Finally, oral administration of MZ-301 robustly and dose-dependently attenuated IFN-γ–induced albuminuria in APOL1 G2HOM mice to baseline levels in a preventative treatment paradigm.

Conclusion

MZ-301 is a potent orally bioavailable small molecule inhibitor of APOL1 pore function that blocks APOL1 lytic activity and reduces APOL1-mediated cytotoxicity in kidney cells. MZ-301 ameliorates proteinuria in a mouse model of APOL1 kidney disease. Together, these findings support inhibition of APOL1 pore function as a precision medicine approach for patients with APOL1 nephropathies and the further development of MZ-301.

Funding

  • Commercial Support