Preclinical testing of RRx-001 in mouse models of experimental endometriosis reveals promising therapeutic impacts

Abstract

Endometriosis is a chronic inflammatory condition characterised by the presence of ectopic endometrial-like tissue (lesions), reduced fertility and chronic pain. Impacting both the health and psycho-social functioning of millions of women worldwide, there is an urgent need for innovative non-hormonal, non-invasive treatments for the disorder. Both peritoneal and lesion-resident macrophages have been strongly implicated in the pathogenesis of endometriosis; key roles include promotion of lesion growth, neuroangiogenesis and nerve sensitization. With such a central role in the disease, macrophages represent a novel therapeutic target. In the current preclinical study, we sought to repurpose the macrophage targeting anti-cancer drug RRx-001 for the treatment of endometriosis. We utilised mouse models of induced endometriosis to demonstrate that RRx-001 induces regression of endometriosis lesions and attenuates pain-like behaviours, without negatively impacting fertility. Targeted depletion of peritoneal cavity macrophages significantly impairs lesion reduction, demonstrating their critical role in mediating the anti-endometriosis impact of RRx-001. Using single nuclei multiomics, we identified a modification of macrophage subpopulations in the peritoneal cavity, specifically reduced acquisition of a pro-disease phenotype and an accumulation of a pro-resolving phenotype. These observations signify the potential of RRx-001 as a novel therapeutic for endometriosis management.