Maze stands at the forefront of an emerging effort to harness the power inherent in the relationship between genes, the protein products encoded by those genes, and specific, observable human traits, and to translate these insights into innovative therapeutics.
Utilizing Maze Compass™, Maze is harnessing the power of human genetics to transform the lives of patients. We are building a broad portfolio of wholly owned and partnered programs, with a focus on genetically informed therapies for common diseases such as chronic kidney disease.
APOL1 kidney disease is a life threatening, genetically driven condition that is estimated to impact close to one million people of West African ancestry in the U.S. alone. All people have two copies of the APOL1 (apolipoprotein L1) gene.
Some individuals of Western or Central African ancestry have genetic mutations in one or both copies of their APOL1 genes (known as the G1 and G2 risk variants) that help protect against trypanosomiasis, a parasitic infection endemic in sub-Saharan Africa also known as African sleeping sickness. Without treatment, African sleeping sickness is frequently fatal.
While this genetic variant protects against a fatal parasitic infection, the long term consequences are that it creates an elevated risk of developing kidney disease and progressing to end stage kidney disease later in life.
We are developing a potential oral medicine to help protect the kidneys from APOL1 kidney disease by blocking the function of the alternate APOL1 proteins produced from the variant APOL1 genes. While the genetic link between APOL1 and kidney disease has been known for over a decade, the mechanism by which it causes kidney disease was not known.
Maze scientists analyzed a new APOL1 genetic variant, now known as N264K, that protects people with the G1 and G2 risk variants, and revealed the details of how APOL1 may cause kidney disease through a series of genetic and biological experiments. Through our research, we have established a better understanding APOL1’s role in kidney disease and how we might intervene with a new product candidate, MZE829, specifically designed to copy the effects of the N264K protective variant.
Our inherited genetic makeup shapes who we are, and it also contributes to the risk of disease throughout our lifetimes. Some genetic variants can increase the risk of certain diseases, while others may provide protection from disease.
The availability of longitudinal genetic and clinical data across millions of individuals around the globe, as well as new technology, cellular engineering and computational tools, have made it practical to identify variations in genes associated with disease, and study how those variations may alter the course of a disease. If we can understand how specific genetic variants protect against a disease, we may be able to mimic those effects and address the specific drivers of that disease, thereby changing outcomes for patients.
Compass™, our end-to-end platform, was purpose-built to capitalize on these advancements in an expedited fashion and is intended to produce a steady stream of targeted medicines for patients. Variant functionalization—looking not just at genetic variation but at the way that genetic variants impact proteins and disease course—is a critical piece of our process that in our view has not yet been fully harnessed in the fields of drug discovery and development. We believe that identifying the right variant in a sea of genetic information, mimicking its beneficial effects, and using these insights to identify those patients most likely to benefit, will translate into life-changing therapies for patients.
NOVEMBER 2023 | MAZE THERAPEUTICS
Small molecule inhibition of APOL1 reverses albuminuria in a chronic mouse model of APOL1 kidney disease American Society of Nephrology Kidney Week 2023OCTOBER 2023 | MAZE THERAPEUTICS Million Veteran Program and Vanderbilt University Medical Center
Genetic Inhibition of APOL1 Pore-Forming Function Prevents APOL1-Mediated Kidney DiseaseMARCH 2023 | MAZE THERAPEUTICS
Muscle glycogen reduction in healthy adults treated with MZE001, an oral inhibitor of GYS1 and potential substrate reduction therapy for Pompe DiseaseFEBRUARY 2023 | MAZE THERAPEUTICS
Results from a first in human study of MZE001, an orally bioavailable inhibitor of glycogen synthase 1 and potential substrate reduction therapy for Pompe DiseaseFEBRUARY 2023 | MAZE THERAPEUTICS
Small molecule inhibition of glycogen synthase I restores autophagolysosomal and metabolic pathway dysfunction in a mouse model of Pompe DiseaseFEBRUARY 2023 | MAZE THERAPEUTICS
Results from a first in human study of MZE001, an orally bioavailable inhibitor of glycogen synthase 1 and potential substrate reduction therapy for Pompe DiseaseFEBRUARY 2023 | MAZE THERAPEUTICS
Quantification of peripheral blood mononuclear cell (PBMC) glycogen as a novel biomarker for therapeutic intervention in Pompe DiseaseFEBRUARY 2023 | MAZE THERAPEUTICS
Small molecule inhibition of glycogen synthase I restores autophagolysosomal and metabolic pathway dysfunction in a mouse model of Pompe diseaseNOVEMBER 2022 | MAZE THERAPEUTICS
Genetic Inhibition of APOL1 Pore Forming Function Prevents APOL1 Kidney DiseaseNOVEMBER 2022 | MAZE THERAPEUTICS
MZ-301 Is a Small Molecule Inhibitor of APOL1 Pore Function That Attenuates Albuminuria in a Mouse Model of APOL1-Mediated Kidney DiseaseJULY 2022 | MAZE THERAPEUTICS
Genetic Inhibition of APOL1 Pore Forming Function Prevents APOL1 Kidney DiseaseFEB 2022 | MAZE THERAPEUTICS
Genetic reduction of muscle glycogen is well tolerated in UK biobank participantsFEB 2022 | MAZE THERAPEUTICS
Pharmacology of small molecule inhibitors of GYS1 in canines and mouse model of Pompe DiseaseFEB 2022 | MAZE THERAPEUTICS
In vitro characterization of MZE001, an orally active GYS1 inhibitor to treat Pompe DiseaseFEB 2022 | MAZE THERAPEUTICS
Substrate reduction therapy for Pompe Disease: Small molecule inhibition of Glycogen Synthase 1 in preclinical modelsJUNE 2021 | EXTERNAL EXPERTS
APOL1 at 10 years: progress and next stepsDECEMBER 2013 | EXTERNAL EXPERTS
APOL1 risk variants, race, and progression of chronic kidney disease.APR 2021 | INTERNAL EXPERT
Identifying therapeutic drug targets using bidirectional effect genesDEC 2019 | EXTERNAL EXPERTS
Are drug targets with genetic support twice as likely to be approvedJUL 2019 | EXTERNAL EXPERTS
Priority index for human genetics and drug discoveryAUG 2016 | MAZE FOUNDER
Leveraging human genetics to guide drug target discoveryFEB 2022 | NATURE
TDP-43 represses cryptic exon inclusion in the FTD–ALS gene UNC13ASEPT 2021 | EXTERNAL EXPERTS
From variant to function in human disease geneticsOCT 2020 | MAZE THERAPEUTICS
A framework to integrate genome-wide CRISPR functional genomics screens with humanJULY 2013 | EXTERNAL EXPERTS
Validating therapeutic targets through human geneticsWe believe that collaborating with exceptional people, academic institutions and industry leaders will be paramount to delivering on our vision of bringing precision medicines to patients.
Do you share our desire to transform the lives of patients by harnessing the power of genetics?
We’d love to hear from you: info@mazetx.com.