RARE Daily

Maze Therapeutics Reveals First Three Programs Targeting Genetic Drivers of Disease

March 23, 2021

Rare Daily Staff

Maze Therapeutics, which came out of stealth mode more than two years ago with $191 million in funding to translate genetic insights into new precision medicines, has revealed its first three lead therapeutic candidates in its pipeline including two rare indications.

The company said it developing a GYS1 targeting Pompe disease therapy, an APOL1 targeting therapy for chronic kidney disease, and a gene therapy targeting amyotrophic lateral sclerosis.

“Since our founding, we have been leveraging insights from leading geneticists, combined with the growing availability of paired human genetic and clinical data, the evolution of functional genomic technologies and advances in computational power, to build our COMPASS platform in order to bring unique insights into efficient, genetics-based drug development,” said Jason Coloma, president and CEO of Maze.

The COMPASS platform combines human genetic data, functional genomic tools, and data science technology to map novel connections between known genes and their influence on susceptibility, timing of onset and rate of disease progression.

Maze says its platform can uncover important new findings for the genetic target and discern which specific signals may be critical for the treatment of patients and which are likely non-actionable. Maze says its pipeline will have the potential to serve as precision medicines for rare diseases and mechanistically defined subsets of common diseases based on certain genetic drivers.

Maze’s therapeutic candidates are designed to target genes with activity that affects the phenotype associated with another, often distant, gene, referred to as genetic modifiers; mimic the activity of protective genetic variants; correct the effects of toxic genetic variants; or leverage new genetic insights to address otherwise challenging drug targets.

Pompe disease is a rare, inherited autosomal recessive disorder that is caused by mutations in the GAA gene, which codes for an enzyme responsible for breaking down lysosomal glycogen into glucose. As a result of this mutation, glycogen accumulates in various tissues, particularly skeletal and cardiac muscle tissues, causing progressive weakness and respiratory insufficiency. Maze is developing a novel, oral approach to treating Pompe disease by inhibiting the protein muscle glycogen synthase, which is encoded by the gene GYS1. Targeting this protein leads to reduction in the synthesis of glycogen, which is expected to restore glycogen balance through a mechanism called substrate reduction.

While GYS1 has been a therapeutic target of interest, its attractiveness as a therapeutic target has been limited due to its structural complexity and uncertainties related to the tolerability of a long-term reduction in muscle glycogen levels. Maze says critical insights derived from its COMPASS platform have enabled the company to overcome these challenges. Maze has interrogated the structurally complex protein to develop an oral inhibitor of muscle glycogen synthase, a target not previously addressable by small molecule therapies. Maze is moving its GYS1 program toward an Investigational New Drug application and expects to initiate clinical trials in the first half of 2022.

Amyotrophic Lateral Sclerosis (ALS) is a rare progressive and fatal neurodegenerative disease with currently available treatments providing only symptomatic relief with limited impact on disease progression. A high variability in disease phenotype and life expectancy is observed and is believed to be related to the presence of genetic modifiers.

One of Maze’s founders, Aaron Gitler, identified a potent genetic modifier, ATXN2, that when inhibited has been shown to limit the toxicity of a certain protein. The protein, TDP-43, is involved in pathologic aggregates seen in up to 97 percent of all ALS cases. Maze is translating these important insights by developing a novel microRNA gene therapy that targets ATXN2 and has used the proprietary application of its functional genomics tools to optimize its properties. Maze plans to name the development candidate in early 2022.

Maze’s third lead program targets chronic kidney disease (CKD), which affects approximately 37 million people in the U.S., including more than 700,000 patients who suffer from end-stage renal disease (ESRD), many of whom require chronic dialysis.

Individuals of African ancestry are at an approximately 3.5-fold greater risk of developing ESRD than individuals of European ancestry. Previous studies have shown that two coding variants of the apolipoprotein L1 (APOL1) encoded by the gene APOL1 cause toxic gain-of-function variants and are important genetic drivers of kidney disease that are responsible for much of the increased risk for CKD and ESRD in individuals of African ancestry. There are currently no approved therapies that address the underlying causes of APOL1-associated CKD, and efficacious treatment options for individuals with APOL1 risk variants and CKD represent a significant unmet medical need.

Maze used its platform to functionalize human genetic variants to uncover the underlying biology of the target and has designed a small molecule that corrects the effects of toxic gain-of-function variants to potentially enable a therapeutic solution. Maze plans to name the development candidate in early 2022.

Besides its three lead candidates, Maze is concurrently leveraging COMPASS to advance additional discovery-stage research programs across three main therapeutic areas of focus: metabolic, cardio/renal and neurological diseases. In addition, Maze is exploring applications of COMPASS in diseases of haploinsufficiency by identifying genetic mechanisms that increase levels of a deficient protein and translating them into therapeutics.

Photo: Jason Coloma, president and CEO of Maze


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