People who share the same disease-causing genetic mutation can have a wide range of severity in their disease. Some don’t get sick at all. Environment can play a role, but with ever-more genetic data available, scientists are unraveling how much other genes can counteract the effect of the main disease-causing gene, too.
Two high-profile biotech venture firms now believe that research into these so-called modifier genes can lead to profitable drugs. Maze Therapeutics is launching today with $191 million from investors led by Third Rock Ventures and Arch Venture Partners, both known for pouring tens of millions of dollars into new high-risk companies.
Maze is looking at diseases where, in rare cases, a modifier gene is improving or even eliminating the symptoms stemming from a disease-causing gene. Maze CEO Charles Homcy, a Third Rock partner, said high-tech genome sleuthing and cutting-edge lab technology like CRISPR-Cas9 can reverse engineer those situations, in essence, and lead the company to medicines that approximate the action of the beneficial gene.
Homcy said the firm has been working behind the scenes for two years and has already pinpointed a few cases of disease-improving modifier genes that are known to researchers. In one case, Maze will develop a small molecule drug that could be in human trials within three years. In another case, Maze will develop a gene therapy. Homcy declined to say which diseases the programs will address.
He did say, however, that Maze will first tackle Mendelian diseases, which are caused by a single mutation in a single gene. There are thousands of these so-called monogenic diseases, most of them rare.
Sickle cell disease is a well-known example of a monogenic disorder that can have milder or nonexistent symptoms, depending upon a patient’s underlying genetic profile. Sickle cell is caused by a single mutation in the gene that produces adult hemoglobin, the oxygen-carrying component of red blood cells. But carriers of that mutation won’t get as sick if they have a second mutation that keeps the fetal hemoglobin gene switched on. Typically, fetal hemoglobin production is mostly switched off after birth.
Using the biology of modifier genes to tackle disease is not a new idea. Here’s a 2010 paper discussing the variable symptoms of cystic fibrosis, a monogenic disease: “Identification of such modifier genes increases our understanding of the elements that affect disease variability and thereby identifies new targets for therapy.”
Homcy acknowledged that Maze is relying in part on widely available knowledge and tools. “Others will take on targets and approaches that we’re doing,” he said. Maze’s advantage, he said, is tapping the expertise of the company’s five scientific founders who are leading researchers in genetics and bioinformatics: Mark Daly of the Broad Institute, Stephen Elledge of Harvard Medical School, Aaron Gitler of Stanford University, Sekar Kathiresan of Harvard and Broad, and Jonathan Weissman of the University of California, San Francisco.
Kathiresan, for example, published a high-profile study last year that advanced the possibility of assessing a patient’s risk of some diseases that are polygenic—that is, driven not by a single genetic mutation but by multiple mutations. Maze could eventually work on medicines that address polygenic diseases, but understanding the role of modifier genes, and setting up experiments to test them, is easier for now with monogenic diseases, Homcy said.
To help make sense of the massive amounts of data that Maze is collecting from several unconnected sources, which aren’t necessarily meant to mesh together, the company has hired Matt Brauer, formerly director of data science and statistical computing at Roche’s Genentech division.
Maze is based in San Francisco. GV, Foresite Capital, Casdin Capital, Alexandria Venture Investments and other investors have joined Third Rock and Arch.