A well-established diabetes drug alleviated brain inflammation in a female mouse model of multiple sclerosis, suggesting the long-used medicine could be repurposed to combat MS in people with female sex chromosomes, who are disproportionately affected by the autoimmune disease.
The results were published in Science Translational Medicine on Oct. 15.
Metformin soothed MS in female, but not male, mice due to its ability to inhibit a gene called Kdm6a, which sits on the X chromosome. When someone has two X chromosomes, their body normally silences one of them so that genes found there are not overexpressed; however, some genes, like Kdm6a, somehow escape this inactivation and are therefore expressed more in people with XX chromosomes than in those with XY chromosomes.
MS is an autoimmune disease where the body attacks its own nerves in the brain and spinal cord, eroding their protective coverings and causing a litany of symptoms that can come and go, including trouble walking, numbness, slurred speech, cognitive issues and more.
Women are about three times more likely than men to develop MS, a pattern that is also seen across other autoimmune diseases like rheumatoid arthritis, lupus and more.
The new study was led by Rhonda Voskuhl, M.D., a neurologist at the University of California, Los Angeles (UCLA), who had previously shown that Kdma6 in circulating T cells is associated with autoimmunity in the same mouse model. In the current study, she wanted to focus on immune cells called microglia in the brain.
“There are 23 or 25 drugs for MS, they all target the immune system,” Voskuhl said. “The Holy Grail of MS is we don't have treatments to combine with an anti-inflammatory that go to the brain.” By targeting microglia, she said, metformin could be that treatment.
Kdm6a controls the expression of a suite of other genes across the genome, with the overall goal of promoting inflammation and immune system activity. Voskuhl’s team conducted an analysis of genetic data from MS patients and found that women with the disease have higher Kdm6a activity than men do, supporting the idea that the gene plays a role in the disease’s sex bias.
Other compounds that also target Kdm6a could have a similar therapeutic effect as metformin, Voskuhl said.
A medicinal chemist may “want something that is really, really highly specific,” she explained, “only blocking Kdm6a and nothing else. They can take this and do that, and I hope they do, because I'm not going to have time to do it.”
Voskuhl won’t have the time because she is busy pursuing metformin itself for use in MS, likely through the launch of a startup in partnership with UCLA. Metformin was first used to treat diabetes in 1957, and it is now included on the World Health Organization’s List of Essential Medicines (PDF) and is one of the most commonly prescribed medications in the U.S.
Her idea is to model a potential new company on CleopatraRx, a company she founded to sell a form of estrogen as a treatment for cognitive symptoms associated with menopause. Estrogen, she told Fierce, has a protective effect against inflammation and aging that balances out the proinflammatory activity of X-linked genes like Kdm6a.
Voskuhl is currently leading a pilot trial at UCLA testing metformin in MS, but the study enrolled both women and men with the disease. Based on what she knows now about metformin’s sex-specific effects in mice, Voskuhl thinks future trials of the drug should focus on women.
While Kdm6a’s role in promoting MS is clear, the disease as a whole has 200 genes associated with it and a range of possible contributing factors, Voskuhl said. Family history, certain infections, sex chromosomes and hormones and more can all influence a person’s chance of developing the disease.
“The bottom line is, sex differences should be used to discover new treatments, and they may need to be tailored for women or tailored for men,” Voskuhl said. “Embrace the differences, discover things for them, and then do clinical trials that target that particular sex.”