CRISPR gene editing is a popular tool among scientists searching for new targets in treating inflammatory diseases. A team at Vanderbilt University Medical Center used the technology to study the role of metabolism in the functioning of immune cells, and they ended up uncovering a target they believe could be exploited to treat several inflammatory diseases.
The CRISPR screen pinpointed MTHFD2, a gene that makes an enzyme vital to the development and functioning of the immune system's T cells. Inhibiting the enzyme or genetically eliminating it was effective in animal models of multiple sclerosis, inflammatory bowel disease (IBD) and allergy, the researchers reported in the journal Immunity.
MTHFD2 is well known in the cancer community, because the enzyme it makes is overexpressed in many tumors. Drugs targeting it had been studied preclinically but never made it into clinical trials.
MTHFD2 is part of what's known as the "one-carbon" metabolism pathway, a series of chemical processes that result in DNA. For the new study, Vanderbilt M.D.-Ph.D. student Ayaka Sugiura inactivated genes in the one-carbon metabolism pathway, one at a time, then introduced cells that were modified in this manner into T cells.
“Ayaka was able to show that inhibiting MTHFD2 doesn’t just stop an immune response, it actually switches it from inflammatory to anti-inflammatory," said Jeffrey Rathmell, Ph.D., professor and director of Vanderbilt's Center for Immunobiology, in a statement.
In addition to blocking the MTHFD2 enzyme in animal models of inflammatory disease, the team investigated whether interfering with the metabolic pathway would hamper the immune response to vaccination. They found that in animal models, inhibiting the enzyme didn't impair the ability of the immune system to respond to vaccines.
Other researchers have used CRISPR gene editing to discover new targets for inflammatory diseases. The IL2RA protein could play a role in Crohn's disease and IBD, scientists at the University of California, San Francisco reported in 2017. After using CRISPR, Salk Institute researchers suggested last year that small-molecule drugs could inhibit the gene Brd9, which in turn would modulate regulatory T cells, potentially offering a new way of treating autoimmune diseases and cancer.
Vanderbilt's Rathmell believes that despite past failures, inhibiting MTHFD2 might indeed work in some cancers. Tumors driven by inflammation, including colon cancer, could be prime candidates, he said.
Rathmell's group is now working to optimize MTHFD2 inhibitors for potential drug development. The researchers also plan to use the same CRISPR-based screening method to study multiple genes in other diseases, they said.