Nature Communications (Jan 2025)
Small molecule APOL1 inhibitors as a precision medicine approach for APOL1-mediated kidney disease
- Brandon Zimmerman,
- Leslie A. Dakin,
- Anne Fortier,
- Evanthia Nanou,
- Angelo Blasio,
- James Mann,
- Howard Miller,
- Marissa Fletcher,
- Tiansheng Wang,
- Suganthini Nanthakumar,
- Gizelle McCarthy,
- Caline Matar,
- Prachi Matsye,
- Guanyu Wang,
- Phillip Snyder,
- Kevin Daniel,
- Harsha Swamy,
- Kelly Sullivan,
- Franklin Bright,
- Audrey Powers,
- Kevin J. Gagnon,
- Fan Lu,
- Steven Paula,
- Suvarna Khare-Pandit,
- Larry Henry,
- Martine Hamel,
- Francois Denis,
- Olivier Nicolas,
- Niresh Hariparsad,
- Shyamesh Kumar,
- Jennifer Proctor,
- Timothy Senter,
- Brinley Furey,
- Mark E. Bunnage
Affiliations
- Brandon Zimmerman
- Vertex Pharmaceuticals Incorporated
- Leslie A. Dakin
- Vertex Pharmaceuticals Incorporated
- Anne Fortier
- Vertex Pharmaceuticals Incorporated
- Evanthia Nanou
- Vertex Pharmaceuticals Incorporated
- Angelo Blasio
- Vertex Pharmaceuticals Incorporated
- James Mann
- Vertex Pharmaceuticals Incorporated
- Howard Miller
- Vertex Pharmaceuticals Incorporated
- Marissa Fletcher
- Vertex Pharmaceuticals Incorporated
- Tiansheng Wang
- Vertex Pharmaceuticals Incorporated
- Suganthini Nanthakumar
- Vertex Pharmaceuticals Incorporated
- Gizelle McCarthy
- Vertex Pharmaceuticals Incorporated
- Caline Matar
- Vertex Pharmaceuticals Incorporated
- Prachi Matsye
- Vertex Pharmaceuticals Incorporated
- Guanyu Wang
- Vertex Pharmaceuticals Incorporated
- Phillip Snyder
- Vertex Pharmaceuticals Incorporated
- Kevin Daniel
- Vertex Pharmaceuticals Incorporated
- Harsha Swamy
- Vertex Pharmaceuticals Incorporated
- Kelly Sullivan
- Vertex Pharmaceuticals Incorporated
- Franklin Bright
- Vertex Pharmaceuticals Incorporated
- Audrey Powers
- Vertex Pharmaceuticals Incorporated
- Kevin J. Gagnon
- Vertex Pharmaceuticals Incorporated
- Fan Lu
- Vertex Pharmaceuticals Incorporated
- Steven Paula
- Vertex Pharmaceuticals Incorporated
- Suvarna Khare-Pandit
- Vertex Pharmaceuticals Incorporated
- Larry Henry
- Vertex Pharmaceuticals Incorporated
- Martine Hamel
- Vertex Pharmaceuticals Incorporated
- Francois Denis
- Vertex Pharmaceuticals Incorporated
- Olivier Nicolas
- Vertex Pharmaceuticals Incorporated
- Niresh Hariparsad
- Vertex Pharmaceuticals Incorporated
- Shyamesh Kumar
- Vertex Pharmaceuticals Incorporated
- Jennifer Proctor
- Vertex Pharmaceuticals Incorporated
- Timothy Senter
- Vertex Pharmaceuticals Incorporated
- Brinley Furey
- Vertex Pharmaceuticals Incorporated
- Mark E. Bunnage
- Vertex Pharmaceuticals Incorporated
- DOI
- https://doi.org/10.1038/s41467-024-55408-2
- Journal volume & issue
-
Vol. 16,
no. 1
pp. 1 – 13
Abstract
Abstract Chronic kidney disease affects ~10% of people worldwide and there are no disease modifying therapeutics that address the underlying cause of any form of kidney disease. Genome wide association studies have identified the G1 and G2 variants in the apolipoprotein L1 (APOL1) gene as major contributors to a subtype of proteinuric kidney disease now referred to as APOL1-mediated kidney disease (AMKD). We hypothesized that inhibition of APOL1 could have therapeutic potential for this genetically-defined form of kidney disease. Here we describe the development of preclinical assays and the discovery of potent and specific APOL1 inhibitors with drug-like properties. We provide evidence that APOL1 channel activity drives podocyte injury and that inhibition of this activity stops APOL1-mediated cell death and kidney damage in a transgenic mouse model. These preclinical data, combined with clinical data from our previously published phase 2 proof-of-concept study, support the potential of APOL1 channel inhibition for the treatment of AMKD.
