Inflammation gene could be a possible drug target for endometriosis | Science

By Rachel FrittsAug 25, 2021, 14:00

Researchers have discovered a potential new way to fight endometriosis, a widespread, mysterious and difficult to treat disease that causes pain and infertility in women. The approach, which emerged after more than two decades of intensive genetic research, blocks a particular gene, thereby reducing discomfort and inflammation, at least in mice.

“It’s really wonderful detective work,” says Linda Griffith, a biological engineer who studies endometriosis at the Massachusetts Institute of Technology. However, she cautions that because the disease is complex, theoretical treatment is likely to relieve symptoms in only a subset of patients. “It brings together so many pieces of the puzzle, but it’s not the last piece.”

Endometriosis affects about one in 10 women. In the disease, the tissue that lines the inside of the uterus – and is shed with each menstrual cycle – also grows. outside uterus. The disease causes severe pain, especially during periods, when the rogue lining tries to come off, creating scar tissue that can essentially stick internal organs together. Only invasive surgery can remove this scar.

Hormonal treatments like estrogen suppressants can alter or disrupt the menstrual cycle, but finding the right one can take months of trial and error. Hormones can also cause a range of side effects, including weight gain, mood swings, and headaches. For some people, these treatments do not help at all.

The new study is a “labor of love” based on research dating back to the 1990s, says team leader Krina Zondervan, an endometriosis researcher at the University of Oxford. At the time, scientists knew that genetics explained part of the risk of getting endometriosis, but they didn’t know which genes were responsible. Next, studies tracking families with multiple cases of endometriosis helped researchers focus on a particular region of chromosome 7.

However, there are hundreds of genes in this region, Zondervan says. Reducing the stretch of the chromosome to a single gene has taken years of detective work. First, her team sequenced DNA from women in 32 families in which three or more women had been diagnosed with endometriosis, focusing on that specific chromosomal region. The group found that many women with more severe cases had variants of a gene called NPSR1. This gene had never been linked to endometriosis, but it has been linked to other inflammatory diseases such as asthma and rheumatoid arthritis.

Zondervan and his colleagues then turned to rhesus macaques, monkeys that also develop endometriosis. When the researchers sequenced the DNA of a group of 850 animals of which 135 had the disease, they saw the same variants. Similar research on more than 3,000 patients with endometriosis and around 7,000 people without the disease confirmed the results, report researchers in Science Translational Medicine today.

The next step was to try to stop the gene from turning on. In mice, researchers blocked the protein that NPSR1 codes by injecting a solution containing a molecule called SHA 68R, known to inhibit gene expression. Mice don’t have their period, but researchers could simulate the pain and inflammation of endometriosis by injecting small pieces of bacteria or uterine lining into their abdomen. Rodents that received SHA 68R experienced less inflammation and abdominal pain. (Mice with abdominal pain shift their weight to their front paws to compensate, and researchers can measure this change in weight.)

“It was a heroic effort,” says Stacy McAllister, an endometriosis researcher at Emory University who was not involved in the study. However, she would like to see more evidence than targeting NPSR1 would help relieve chronic pain rather than short-term pain relief.

A complicating factor is that not all patients with endometriosis had NPSR1 variant, the researchers found. “That’s why it’s so hard to make progress on this disease,” Griffith says. “Endometriosis is most likely not a disease. Studies like this help researchers understand the complex disease and how to treat it, she says.

The researchers then want to target the gene in monkeys to see if it has the same benefits. “It was a big project and a long effort,” says Thomas Tapmeier, endometriosis researcher at Monash University and lead author of the study. “This is just the end of the beginning.”