New hormone receptor strategy offers targeted treatment for lupus

Researchers at the University of California, Riverside and City of Hope have identified a new strategy for treating systemic lupus erythematosus (SLE), or lupus, an autoimmune disease in which the immune system attacks healthy tissues. By targeting an imbalance in receptors for the hormone prolactin in disease-causing immune cells, the team reduced inflammatory molecules and harmful immune cells while preserving their normal counterparts.

Prolactin acts as a signaling molecule in many tissues throughout the body. Previous clinical evidence has linked the hormone to lupus, but the mechanisms behind the relationship have remained unclear. The study, published in Experimental and Molecular Medicine and done in human cells and mouse models, points to an important role for a specific form of the prolactin receptor in lupus. 

Ameae Walker, a professor of biomedical sciences in the UCR School of Medicine and co-corresponding author of the study, explained that prolactin receptors are produced in two main varieties, long and short. They both bind prolactin via identical regions outside the cell but produce different signaling inside the cell.

"In immune cells from patients with lupus, the balance is shifted toward the long form," she said. "The long-form prolactin receptor is not a mutant; it's a perfectly normal form of the receptor. But its expression, and its ratio with the short form, is abnormal in pathogenic immune cells in lupus."

To address this imbalance, the team developed splice-modulating oligomers (short, synthetic DNA sequences) to alter how cells produce prolactin receptors. These molecules interfere with the processing of receptor messenger RNA and prevent cells from producing the long receptor form while allowing them to continue producing the short forms, which are important in healthy tissues, including the brain and liver.

"This approach could offer an advantage over antagonists and antibodies, which cannot distinguish between the two receptor isoforms because their extracellular regions are identical," Walker said.

Lupus develops when the immune system produces autoantibodies that attack the body's own tissues, triggering inflammation and potentially damaging organs. The disease affects people differently, but kidney involvement is common and can have serious consequences. The researchers found their treatment reduced kidney damage in mouse models.

This suggests that rebalancing prolactin receptor isoforms could potentially control disease activity and reduce the risk of organ damage."

Srividya Swaminathan, co-corresponding author, associate professor of systems biology, City of Hope

According to Walker and Swaminathan, preventing organ damage without suppressing healthy immune cells would be a significant therapeutic advance. Current lupus treatments suppress broad parts of the immune system, leaving patients vulnerable to infections and other complications. Drugs that curb prolactin release from the pituitary gland help only some patients, because many other tissues also produce the hormone.

"We initially didn't understand the different roles of the two types of prolactin receptors," Swaminathan said. "If targeting only the long type could prevent kidney damage in patients with lupus, it could represent a major advance. As our results remain preclinical, further validation and testing is required before the approach can be evaluated in patients."

Before clinical trials can begin, the treatment must be produced and tested under rigorous manufacturing, quality-control and regulatory standards. Walker and Swaminathan are seeking an industry partner to advance the splice-modulating oligonucleotides through preclinical testing and regulatory review.

The collaboration between Walker and Swaminathan began through a City of Hope–UC Riverside Biomedical Research Initiative (CUBRI) grant. It has since been funded by a MERIT Award from the National Cancer Institute and by awards from the National Institute of Arthritis and Musculoskeletal and Skin Diseases, Concern Foundation, Prevent Cancer Foundation, American Society of Hematology, and University of California Drug Discovery Consortium.

UCR holds the original patent for the long-form prolactin receptor splice-modulating oligonucleotide. A pending follow-on application, listing Walker and Swaminathan as inventors, covers its use to treat and prevent B-cell disorders, including lupus.