Targeting hormone receptors reduces lupus-related kidney damage in mice

Researchers at the University of California, Riverside and City of Hope have discovered a promising approach to mitigating kidney damage linked to lupus in mice. The team focused on an imbalance in receptors for the hormone prolactin in disease-causing immune cells. By targeting the long form of the prolactin receptor, they were able to reduce inflammatory markers and harmful immune cells without affecting normal counterparts.

Prolactin, a signaling molecule present in various body tissues, has been previously associated with lupus, although the precise mechanisms were unclear. The study, published in Experimental and Molecular Medicine, investigated human cells and mouse models, highlighting the crucial role of a particular prolactin receptor form in lupus.

The long-form prolactin receptor, though not mutated, shows abnormal expression and ratio with the short form in pathogenic immune cells of lupus patients. To address this imbalance, the researchers developed splice-modulating oligomers, synthetic DNA sequences that interfere with the production of the long receptor form while allowing the short form to continue being produced.

This method may offer a more targeted treatment compared to existing antagonists and antibodies, which cannot differentiate between the two receptor isoforms due to identical extracellular regions. The study's findings suggest that rebalancing prolactin receptor isoforms could control disease activity and minimize the risk of organ damage in lupus patients.

Current treatments suppress broad immune system parts, leaving patients vulnerable to infections and other complications. While the approach remains preclinical, the researchers are seeking an industry partner to advance the splice-modulating oligonucleotides through preclinical testing and regulatory review. The original patent for the long-form prolactin receptor splice-modulating oligonucleotide is held by UCR, and a pending application covers its use in treating and preventing B-cell disorders, including lupus.