SOUTH SAN FRANCISCO, Calif.--(BUSINESS WIRE)--Maze Therapeutics, a company translating genetic insights into new precision medicines, today announced the publication of research validating the protective role and mechanism of an APOL1 genetic variant– p.N264K— in chronic kidney disease (CDK) and end stage kidney disease (ESKD) among carriers with high-risk variants. The research was published online, in the Journal of the American Society of Nephrology (JASN) in collaboration with the Million Veteran Program and Vanderbilt University Medical Center.
Apolipoprotein L1 (APOL1) is a protein encoded by the APOL1 gene in humans. Genetic variants of the gene (G1 and G2) are associated with increased risk for a spectrum of progressive kidney diseases in people of African ancestry. Maze researchers, along with their collaborators, previously identified and described the protective role and mechanism of a genetic variant in APOL1– p.N264K– in which presence of the variant was shown to reduce conductance of ions through the APOL1 pore thereby suppressing the toxicity of APOL1 in kidney cells and disease progression.
“While the genetic link between APOL1 and kidney disease has been well-established, the mechanism by which it induces kidney injury had remained uncertain for nearly a decade,” said Harold Bernstein, M.D., Ph.D., president, research and development, and chief medical officer of Maze. “Through this research and earlier research conducted at Maze, we have established a better understanding of APOL1’s mechanism in kidney disease and how we may be able to intervene with a medical therapy. Based on these findings, our lead program for APOL1 kidney disease was designed to phenocopy the protective variant, mimicking the protective characteristics of the p.N264K variant, as a potential disease modifying treatment for a large sub-population of patients suffering from kidney disease.”
To further validate their finding, the researchers conducted a cross-sectional analysis of 121,492 participants of African ancestry from the Million Veterans Program to determine if the presence of p.N264K modified the association between the G1/G2 risk variants and CKD and ESKD. The results showed a clear association between p.N264K and a significantly reduced risk of CKD and ESKD among carriers of the G1/G2 risk variants compared to individuals with APOL1 high-risk genotypes. The results were further replicated by the researchers through analyses from the Vanderbilt University Biobank (n= 14,386) and the National Institutes of Health All of Us (n= 14,704). Variant functionalization studies in cell models were also conducted, which showed that APOL1 p.N264K blocked APOL1 pore-forming function and ion conductance and reduced toxicity of APOL1 high-risk mutations.
These findings further support Maze’s planned advancement of a small molecule APOL1 inhibitor program, which the Company plans to evaluate as a treatment for APOL1 kidney disease, with a Phase 1 trial anticipated to begin by the end of 2023.
About Maze Therapeutics
Maze Therapeutics is a biopharmaceutical company harnessing the power of human genetics to transform the lives of patients. The Company is committed to developing breakthrough precision medicines for common diseases with large unmet medical needs. Maze has developed Maze CompassTM, a proprietary, purpose-built platform to leverage genetic variation and integrate the critical step of variant functionalization into each stage of therapeutic development. Utilizing Maze CompassTM, the Company's strategy is to develop its therapies independently, in collaboration with major pharmaceutical companies, and through company formation. For more information, please visit mazetx.com, or follow us on LinkedIn and X.
