Small molecule APOL1 inhibitors as a precision medicine approach for APOL1-mediated kidney disease
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 cont...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-55408-2 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Brandon Zimmerman |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-d3abf4c5a7724e19a5dd87eb45a093af |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-d3abf4c5a7724e19a5dd87eb45a093af2025-01-05T12:39:57ZengNature PortfolioNature Communications2041-17232025-01-0116111310.1038/s41467-024-55408-2Small molecule APOL1 inhibitors as a precision medicine approach for APOL1-mediated kidney diseaseBrandon Zimmerman0Leslie A. Dakin1Anne Fortier2Evanthia Nanou3Angelo Blasio4James Mann5Howard Miller6Marissa Fletcher7Tiansheng Wang8Suganthini Nanthakumar9Gizelle McCarthy10Caline Matar11Prachi Matsye12Guanyu Wang13Phillip Snyder14Kevin Daniel15Harsha Swamy16Kelly Sullivan17Franklin Bright18Audrey Powers19Kevin J. Gagnon20Fan Lu21Steven Paula22Suvarna Khare-Pandit23Larry Henry24Martine Hamel25Francois Denis26Olivier Nicolas27Niresh Hariparsad28Shyamesh Kumar29Jennifer Proctor30Timothy Senter31Brinley Furey32Mark E. Bunnage33Vertex Pharmaceuticals IncorporatedVertex Pharmaceuticals IncorporatedVertex Pharmaceuticals IncorporatedVertex Pharmaceuticals IncorporatedVertex Pharmaceuticals IncorporatedVertex Pharmaceuticals IncorporatedVertex Pharmaceuticals IncorporatedVertex Pharmaceuticals IncorporatedVertex Pharmaceuticals IncorporatedVertex Pharmaceuticals IncorporatedVertex Pharmaceuticals IncorporatedVertex Pharmaceuticals IncorporatedVertex Pharmaceuticals IncorporatedVertex Pharmaceuticals IncorporatedVertex Pharmaceuticals IncorporatedVertex Pharmaceuticals IncorporatedVertex Pharmaceuticals IncorporatedVertex Pharmaceuticals IncorporatedVertex Pharmaceuticals IncorporatedVertex Pharmaceuticals IncorporatedVertex Pharmaceuticals IncorporatedVertex Pharmaceuticals IncorporatedVertex Pharmaceuticals IncorporatedVertex Pharmaceuticals IncorporatedVertex Pharmaceuticals IncorporatedVertex Pharmaceuticals IncorporatedVertex Pharmaceuticals IncorporatedVertex Pharmaceuticals IncorporatedVertex Pharmaceuticals IncorporatedVertex Pharmaceuticals IncorporatedVertex Pharmaceuticals IncorporatedVertex Pharmaceuticals IncorporatedVertex Pharmaceuticals IncorporatedVertex Pharmaceuticals IncorporatedAbstract 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.https://doi.org/10.1038/s41467-024-55408-2 |
| spellingShingle | 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 Small molecule APOL1 inhibitors as a precision medicine approach for APOL1-mediated kidney disease Nature Communications |
| title | Small molecule APOL1 inhibitors as a precision medicine approach for APOL1-mediated kidney disease |
| title_full | Small molecule APOL1 inhibitors as a precision medicine approach for APOL1-mediated kidney disease |
| title_fullStr | Small molecule APOL1 inhibitors as a precision medicine approach for APOL1-mediated kidney disease |
| title_full_unstemmed | Small molecule APOL1 inhibitors as a precision medicine approach for APOL1-mediated kidney disease |
| title_short | Small molecule APOL1 inhibitors as a precision medicine approach for APOL1-mediated kidney disease |
| title_sort | small molecule apol1 inhibitors as a precision medicine approach for apol1 mediated kidney disease |
| url | https://doi.org/10.1038/s41467-024-55408-2 |
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