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Maze Therapeutics Uses CRISPR to Identify Genetic Modifiers That Could Lead to Precision Medicine Companion Diagnostics for Clinical Laboratories

With $191 million in startup capital, the genomics startup will draw on existing genetic databases to create personalized medicine therapies for chronic diseases

Why do some people get sick while others do not? That’s what genetic researchers at Maze Therapeutics want to find out. They have developed a new approach to using tools such as CRISPR gene editing to identify and manipulate proteins in genetic code that may be the key to providing personalized protection against specific diseases.

If viable, the results of Maze’s research could mean the development of specific drugs designed to mimic genetic code in a way that is uniquely therapeutic to specific patients. This also would create the need for clinical laboratories to sequence and analyze patients’ DNA to determine whether a patient would be a candidate for any new therapies that come from this line of research.

Such developments are at the heart of precision medicine. It promises to bring companion diagnostics to clinical laboratories that will help anatomic pathologists employ disease therapies keyed to each patient’s unique physiology.

Natural Protection Against Disease

Based in San Francisco, Maze Therapeutics (Maze) is studying modifier genes—genes that affect the phenotype or physical properties of other genes—and attempting to create drugs that replicate them, reported MIT Technology Review. Maze believes that genetic modifiers could afford a “natural form of protection” against disease.

“If you have a disease-causing gene, and I have the disease-causing gene, why is it that you may be healthy and I may be sick? Are there other genes that come into play that provide a protective effect? Is there a drugging strategy to recover normal phenotype and recover from the illness?” Maze Chief Executive Officer Jason Coloma, PhD, asked in an interview with FierceBiotech.

In 2019, Maze received $191 million in financing from Third Rock Ventures, ARCH Venture Partners, and others, to find ways to translate their findings into personalized medicines, according to a news release. And with the availability of international public genetic databases and CRISPR gene editing, now may be good timing.

“This was the perfect time to get into this space with the tools that were being developed and the amount of data that has been accumulated on the human genetic side,” Charles Homcy, MD, Third Rock Ventures Partner and Maze Scientific Founder, told Forbes, which noted that Maze is tapping existing population-wide genetic databases and large-scale studies, including the United Kingdom’s Biobank and Finland’s Finngen.

To help find genetic modifier drug targets, Maze is accessing CRISPR gene editing capabilities. Jonathan Weissman, PhD, Maze Scientific Founder and Professor of Cellular Molecular Pharmacology at University of California, San Francisco (UCSF), told MIT Technology Review: “You take a cell with a disease-causing gene and then see if you can turn it back to normal. We can do 100,000 experiments at once because each cell is its own experiment.”

“At Maze, we are focused on expanding our understanding of the natural disease protection provided by genetic modifiers through an integrated approach that combines studying natural human genetic variation across the globe and conducting large-scale experiments of gene perturbations,” Charles Homcy, MD (above), Founder and interim CEO of Maze and a partner at Third Rock Ventures, said in a news release. “Through our integrated approach, we believe we will create novel medicines based around those modifiers to treat a number of diseases.” (Photo copyright: Forbes.)

Using CRISPR to Identify the Cause of Disease

One drug research program reportedly progressing at Maze involves developing gene therapy for the neurogenerative disease amyotrophic lateral sclerosis (ALS). The program borrows from previous research conducted by Aaron Gitler, PhD, Professor of Genetics at Stanford University and Maze co-founder, which used CRISPR to find genetic modifiers of ALS. The scientists found that when they removed the protein coding gene TMX2 (Thioredoxin Related Transmembrane Protein 2), the toxicity of proteins building the disease was reduced, reported Chemical and Engineering News.

“We used the CRISPR-Cas9 system to perform genome-wide gene-knockout screens for suppressors and enhancers of C9ORF72 DPR toxicity in human cells,” Gitler and colleagues wrote in Nature Genetics. “Together, our results demonstrate the promise of using CRISPR-Cas9 screens in defining the mechanisms of neurodegenerative diseases.”

In 2020, Maze plans to advance elements of its ALS research to a Food and Drug Administration Investigational New Drug (IND) application. Maze also intends to work next year on drugs targeting metabolism, kidney, and glaucoma, FierceBiotech reported.

“We have the flexibility to think differently. We like to think of ourselves as part of this new breed of biotech companies,” Coloma told FierceBiotech.

It’s an exciting time. Clinical laboratories can look forward to new precision medicine diagnostic tests to detect disease and monitor the effects of patient therapies. And the research initiatives by Maze and other genetic companies represent a new approach in the use of genetic code to create specific drug therapies targeted at specific diseases that work best for specific patients.

The companion diagnostics that may come from this research would be a boon to anatomic pathology.

—Donna Marie Pocius

Related Information:

The Secret to a New Drug Could be Hiding in Your Genes: Companies are Searching Gene Databases for People Whose DNA Says They Should be Very Sick, But Who Aren’t

Special Report: Maze Therapeutics

Maze Therapeutics Launches with $191 Million to Focus on Translating Genetic Insights into New Medicines

Third Rock and ARCH-Backed Genetics Startup Launches with Nearly $200 Million

Maze Therapeutics Raises $191 Million

CRISPR Screen Identifies Genetic Modifiers of ALS

CRISPR-Cas9 Screens in Human Cells and Primary Neurons Identify Modifiers of C90RF72 Dipeptide-Repeat-Protect Toxicity