Maze Therapeutics Advances Potential Gene Therapy Involving ATXN2

Maze Therapeutics is advancing the development of a lead gene therapy candidate for amyotrophic lateral sclerosis (ALS), which works by suppressing the activity of a potent genetic modifier called ATXN2.

Genetic modifiers are genes or genetic variants that can increase or reduce the severity of a condition without necessarily causing the disease themselves. Such modifiers are thought to contribute to the variability in clinical symptoms and disease progression observed in ALS patients.

The company’s other lead candidates include two oral therapies: one for Pompe disease (a rare, progressive neuromuscular disorder) and the other for chronic kidney disease.

Maze was created with a “bold vision — to leverage growing knowledge of genetic drivers of disease in order to create precision medicines for the treatment of both rare and more common diseases,” Jason Coloma, PhD, Maze’s president and CEO, said in a press release.

“We are excited to advance these initial programs and look forward to continued progress toward the clinic as efficiently as possible,” said Sarah Noonberg, MD, PhD, Maze’s chief medical officer.

In 2010, one of Maze’s founders, Aaron Gitler, PhD, and his team identified the ATXN2 gene as a potent genetic modifier of the toxic TDP-43 protein clumps that are present in up to 97% of all ALS cases and are thought to be an important driver of the disease.

Subsequent studies showed that a certain level of expansion of specific sequences of the ATXN2 gene increases the risk of ALS and is associated with some sporadic cases of ALS.

Since suppressing ATXN2 was shown to limit TDP-43 toxicity in several animal models, Maze is developing an ATXN2-targeting microRNA gene therapy.

MicroRNAs are small RNA molecules that target a specific gene’s messenger RNA — the intermediate molecule derived from DNA that guides protein production — to prevent generation of that protein.

The company plans to name the ALS treatment candidate in early 2022.

All three candidates, still in preclinical stages of development, were the result of findings generated through Maze’s proprietary COMPASS platform, which helped uncover key information regarding the genetic target. It discerns which specific signals may be critical for the treatment of patients and which are the most targetable.

The platform combines human genetic data, functional genomic tools, and data science technology to identify new links between known genes and clarify their influence on a person’s susceptibility to a disease, and on disease onset and progression.

“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 [therapy] development,” Coloma said.

Noonberg noted that COMPASS-derived insights “helped fill in fundamental data gaps, turning known but challenging targets into exciting, differentiated approaches to the genetic drivers of disease for our first three programs.”

While potential therapeutic targets identified using human genetic data are “more likely to yield efficacious treatments, very few groups have had the capabilities to then turn genetic insights into viable [therapy] programs,” Noonberg added.

“We believe our COMPASS platform, integrated with our extensive [therapy] discovery capabilities, will allow us to accelerate the pace of therapeutic development, as well as increase the likelihood of producing therapies that provide meaningful clinical benefit for patients,” she said.

Maze’s treatment candidates are designed to either target 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 therapy targets.

“We are excited by the significant progress we have made with our platform and pipeline, bringing us an important step closer to our goal of delivering the right [therapy] to the right patient at the right time,” Coloma said.

The company also is using COMPASS to advance additional discovery-stage research programs across three main therapeutic areas of focus: metabolic diseases, cardiovascular/kidney conditions, and neurological diseases.