Neuropeptide S Receptor 1 Is a Target for Nonhormonal Therapy of Endometriosis

Science Translational Medicine 2021, August 25:.

Vol. 13, Issue 608, eabd6469

DOI: 10.1126 / scitranslmed.abd6469

Commentary

Endometriosis is a chronic inflammatory disease with pelvic pain and infertility as symptoms, limited treatment options, and a 50% heritability.

This study was conducted to identify therapeutic targets using genetic analysis of two naturally occurring endometriosis species, human and rhesus monkey.

It seems that they decided to sequence DNA from 32 human families that contribute to the genetic linkage signal of chromosome 7p13-15 and observe a significant overexpression of a predicted harmful low frequency coding variant in NPSR1, the gene that encodes the neuropeptide S receptor 1 in cases (mostly stage III / IV).

Significant linkage to human 7p13-15 and orosologous regions was replicated in a pedigree of 849 rhesus monkeys (P= 0.0095).

Target association analysis in 3194 surgically confirmed unrelated cases and 7060 controls revealed that the common insertion/deletion variant rs142885915 was significantly associated with stage III/IV endometriosis.

Immunohistochemistry, qRT-PCR, and flow cytometry experiments showed that NPSR1 is expressed in glandular epithelium from orthotopic and ectopic endometrium, and in monocytes in peritoneal fluid.

The NPSR1 inhibitor SHA68R blocked NPSR1-mediated signaling, pro-inflammatory TNF-α release, and monocyte chemotaxis in vitro (P < 0.01) and resulted in a significant reduction in inflammatory cell infiltration and abdominal pain

The study concludes that the NPSR1 / NPS system is a genetically validated, non-hormonal target for the treatment of endometriosis and is likely to be of increasing relevance to stage III / IV disease.