Sometimes genetic diseases are not as straightforward as they seem. Charles Homcy learned that firsthand more than four decades ago when he was a medical student at Johns Hopkins University.
During his training, Homcy recalls seeing children from the same family who carried the same genetic mutations but whose health had dramatically diverged. For example, he saw pairs of children with sickle-cell disease, a condition caused by a single mutation in a gene for hemoglobin. One child with the mutation was gravely ill—with the worst symptoms of anemia, pain, and stroke—while another child was essentially fine. No one knew why.
Researchers have since cracked that medical mystery: A mutation in a different gene cancels out the harmful effects of the hemoglobin mutation. This story, and ones like it, have spurred scientists to search for other mutations that effectively cancel out the harmful effects of disease-causing mutations. These disease-sparing mutations are yielding new clues for drug discovery, and they’re at the heart of a well funded biotech start-up that Homcy now leads.
That company, called Maze Therapeutics, is making a splash today by announcing that it has raised $191 million from a suite of private investors including Third Rock Ventures, ARCH Venture Partners, Google’s venture arm GV, and others. It’s the third drug company to launch with more than $100 million this year.
Maze has been more than three years in the making behind closed doors at Third Rock, where Homcy has worked since 2010. The goal of the company is to develop drugs based on genetic modifiers, the term geneticists use for one gene that alters the function of another. In the sickle-cell disease example, the genetic modifier was a gene called BCL11A. A mutation in this gene causes children and adults with sickle-cell disease to continue producing the fetal version of hemoglobin, allowing them to live relatively healthy lives despite mutation in their regular hemoglobin.
Homcy’s new company isn’t working on sickle-cell disease, although other companies, including Crispr Therapeutics, are hoping to treat the disease by intentionally introducing a mutation in BCL11A. At Maze, Homcy hopes to broadly capitalize on the concept of genetic modifiers as an untapped area of drug discovery.
He’s recruited five high-profile geneticists as scientific cofounders to lend their expertise on genetic diseases and on designing tools to discover new genetic modifiers, including Stephen Elledge of Harvard Medical School and Jonathan Weissman of the University of California, San Francisco.
To discover new genetic modifier drug targets, Maze will use a general approach called functional genomics, in which scientists use tools like CRISPR or RNA interference to knock down genes and observe what happens to a cell. “CRISPR is making it a lot easier to do this,” Homcy says.
He has big ambitions for Maze, and with cash in hand, he plans to hit the ground running. “When we started Maze, it was important for us to do two things,” Homcy says. One was to get a few drug-discovery programs rolling right away; the other was to build up the firm’s platform for discovering genetic modifier targets and drugs. “Both of these things require money, and that’s why we raised the amount of money we did, so we wouldn’t have to sacrifice one or the other.”
Maze isn’t disclosing many details about its inner workings yet, but Homcy says the firm already has three drug programs under way. The first is for a small molecule that drugs an enzyme involved in a genetic disease.
A second drug program, which Homcy says is not a small molecule, targets a protein involved in a neurodegenerative disease. That program might borrow a play from one of Maze’s cofounders, Stanford University neuroscientist Aaron Gitler. Last year Gitler’s lab used a CRISPR screen to discover new genetic modifiers of amyotrophic lateral sclerosis. One was a gene called TMX2. Knocking out TMX2 reduced the toxicity of proteins that build up in cell models of the disease (Nat. Genet. 2018, DOI: 10.1038/s41588-018-0070-7).
Maze’s third drug program is related to the kidneys, but Homcy won’t say more.
Although Maze has a chemistry team, “we are not committed to small molecules,” Homcy says. The firm will also consider biologics, gene therapies, and approaches like RNA interference and antisense oligonucleotides—which can be used to knock down genes. “We’ll do what’s necessary to get the job done,” he adds. “We’re tool agnostic.”
Although Maze will be juggling three diverse drug programs while simultaneously building up its genetic modifier discovery platform, Homcy brushes off concerns about a lack of focus. The firm’s large fundraising should enable it to tackle them all, he says.
“You can really get killed in these kinds of companies when you don’t have the capitalization to begin with and when you don’t have investors that are committed to the vision,” Homcy says. “And I think we have both here, so hopefully we can execute.”