Inflammation gene may be possible drug target for endometriosis

Research conducted by the University of Oxford, Baylor College of Medicine, the University of Wisconsin-Madison, and Bayer AG has discovered a potential new way to fight endometriosis. The approach—which came to light after more than two decades of intensive genetic research—blocks a particular gene, reducing pain and inflammation, at least in mice.

The researchers performed genetic analyses of humans and rhesus macaques to identify a specific gene, neuropeptide S receptor 1 (NPSR1), that increases risk of suffering pain from endometriosis.

The results reveal a potential new non-hormonal drug target that may lead to improved therapies in endometriosis. Their results are published in Science Translational Medicine [1].

Building upon previous genetic research in endometriosis

The Oxford team, led by Professor Krina Zondervan, had previously found a genetic linkage to endometriosis on chromosome 7p13-15 by analysing DNA from families containing at least three women diagnosed with endometriosis.

The Baylor team, led by Dr Jeffrey Rogers, verified this genetic linkage in the DNA of rhesus monkeys with spontaneous endometriosis at the Wisconsin National Primate Research Center at the University of Wisconsin-Madison.

This validation justified further research through in-depth sequencing analysis of the endometriosis families at Oxford, which narrowed down the genetic cause to rare variants in the NPSR1 gene. Most of the women carrying these rare variants had stage III/IV disease.

The Baylor researchers similarly sequenced rhesus monkeys and again showed suggestive evidence also in this species. Finally, an Oxford study of more than 11,000 women, including patients with endometriosis and healthy women, identified a specific common variant in the NPSR1 gene also associated with stage III/IV endometriosis.

Jeffrey Rogers
Associate Professor, Department of Molecular and Human Genetics, Baylor College of Medicine

This is one of the first examples of DNA sequencing in nonhuman primates to validate results in human studies and the first to make a significant impact on understanding the genetics of common, complex metabolic diseases.

said Jeffrey Rogers.

The primate research really helped to provide confidence at each step of the genetic analysis in humans and gave us motivation to carry on chasing these particular genes.

Potential new targeted treatment in endometriosis

The insights revealed in this genetic analysis point to a potential new drug target.

As part of this collaboration, researchers at Bayer, in scientific partnership with Oxford University, used an NPSR1 inhibitor to block protein signalling of that gene in cellular assays and then in mouse models of endometriosis.

They found this treatment led to reduced inflammation and abdominal pain, thus identifying a target for future research in treating endometriosis. (Mice experiencing abdominal pain shift their weight toward their front paws to compensate, and researchers can measure that weight shift.)

Professor Krina Zondervan
Chair of the department of women’s and reproductive health, University of Oxford

Said Krina Zondervan:

This is an exciting new development in our quest for new treatments of endometriosis, a debilitating and under recognised disease affecting 190 million women worldwide.

We need to do further research on the mechanism of action and the role of the genetic variants in modulation of the gene’s effects in specific tissues. However, we have a promising new non-hormonal target for further investigation and development that appears to address directly the inflammatory and pain components of the disease.

Reference
  1. Tapmeier T, Rahmioglu N, et al. Neuropeptide S receptor 1 is a nonhormonal treatment target in endometriosis. Sci Transl Med 2021;13(608)
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