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Endometriosis Treatment Target Proposed From Genetic Analysis

NEW YORK – A new genetic study in humans and rhesus macaques has highlighted the possibility of targeting the neuropeptide S receptor 1-coding gene NPSR1 to treat spontaneous endometriosis, particularly more advanced forms of the chronic inflammatory disease.

"Our results suggest the NPSR1/NPS system as a genetically validated, non-hormonal target for the treatment of endometriosis, with likely increased relevance to stage III/IV endometriosis therapeutics," co-first and co-corresponding author Thomas Tapmeier, a researcher affiliated with the University of Oxford and Monash University's obstetrics and gynecology department, and his colleagues wrote in a paper published in Science Translational Medicine on Wednesday.

They noted that past studies put the heritability of endometriosis — a painful, fertility-affecting disease marked by endometrial tissues from the uterine lining that extend into other parts of the body — at roughly 50 percent, though many of the specific genetic contributors to the condition have yet to be unearthed, leaving patients with relatively limited treatment options.

"Apart from painkillers or surgery, endometriosis is treated by shutting down the hormonal cycle entirely," Tapmeier said in an email. "However, women and couples who want children need other options."

For their study, he and his colleagues first did fine-mapping analyses of a chromosome 7 region previously implicated in endometriosis in individuals from 32 families with three or more endometriosis-affected family members apiece, focusing in on a 5-megabase stretch of sequence that was subsequently assessed by targeted sequencing in more than 100 women with endometriosis and five unaffected controls from endometriosis-affected families.

With this approach, the team uncovered low-frequency, missense variants in the G protein-coupled cell surface receptor-coding gene NPSR1 that were significantly linked to disease. After validating the findings in a rhesus macaque pedigree made up of 849 representatives — and with array-based genotyping on almost 3,200 human endometriosis cases and 7,060 controls — it also tracked down a more common insertion-deletion variant with ties to stage III or IV endometriosis cases.

"We were fortunate in that one of the 'hits' from our genetic screens was the gene for the NPSR1 receptor, which had previously been implied in conditions like asthma, inflammatory bowel disease (IBD) and recurrent abdominal pain (RAB)," Tapmeier explained in an email.

"[I]t made sense that NPSR1 might have a role in endometriosis, too," he added. "Often, however, the genes revealed are not as straightforward to target or even conceivably connect to the condition."

To explore that possibility, the team turned to RT-PCR, immunohistochemistry, flow cytometry, and other approaches to further characterize NPSR1 expression and other features in affected or unaffected endometrial tissue or in immune monocyte cells from corresponding peritoneal fluid, before looking at the consequences of NPSR1 inhibition in a mouse model of endometriosis.

There, the researchers reported, pain symptoms and inflammation in the peritoneal region were stanched by dialing down NPSR1 signaling with a compound called SHA 68R. Based on such findings, they suggested that a similar approach could eventually lead to a non-hormonal treatment option for endometriosis.

While results from the current study provide evidence that treatments targeting NPSR1 can stanch inflammatory and pain symptoms in mouse models of endometriosis, Tapmeier noted that the specific inhibitor used in the mouse experiments is not expected to be a suitable drug for humans in the clinic, suggesting further efforts are needed to not only explore apparent NPSR1 ties to endometriosis but also find and test such a compound.

"[T]he inhibitor we used here is not suitable as a drug in the clinic," he said. "[I]t merely served as 'tool compound.' The next aim now is to find a drug that could be used in the clinic eventually — and how NPSR1 is exactly connected to endometriosis."