The study was published recently online ahead of print by the journal Arthritis & Rheumatism.
The study showed the compound, known as SR2211, blocked development of virtually all symptoms of rheumatoid arthritis in mice within the first eight to ten days of treatment. The mice also showed significantly reduced bone and cartilage erosion compared to animals that did not receive treatment.
The experimental compound targets the nuclear receptor RORγ, a key regulator of TH17 cells, one of a family of white blood cells that play a role in the immune system. Identified only a decade ago, TH17 cells have been implicated in numerous autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease and lupus.
“This compound, and its precursors, showed the ability to block the release of specific inflammatory mediators from Th17 cells in culture, so we were confident that SR2211 would demonstrate good efficacy in rodent models of autoimmune disease,” said biochemist Patrick R. Griffin, chair of the TSRI Department of Molecular Therapeutics. “Our newest study strongly supports the idea that by targeting the RORγ receptor, we can therapeutically repress inflammation and joint destruction associated with rheumatoid arthritis.”
While several treatments are currently available for rheumatoid arthritis, Griffin noted their use is associated with the increased risk of infections and pneumonia. Since they have to be taken by injection, they are optimized for long, sustained immunosuppressive action, which is a disadvantage in managing opportunistic infections. An oral medication could be taken daily and stopped immediately to allow the drug to leave the body in the case of a potentially life-threatening infection.
“This study with SR2211 shows that repressing the activity of the RORγ receptor alone works to reduce joint erosion and inflammation,” Griffin said. “It’s an alternative mechanism of action that can provide doctors with additional treatment options for patients who do not respond well or cannot tolerate current therapies.”
“We wanted to develop a compound with the potential to help treat patients suffering from a range of autoimmune diseases, including rheumatoid arthritis,” said Staff Scientist Mi Ra Chang, the first author of the study and a member of the Griffin lab. “Compounds such as SR2211 work directly and specifically on at least two immune cell types directly involved in the pathogenesis of autoimmune disease.”
In addition to Griffin and Chang, other authors of the study, “Pharmacological Repression of RORγ Is Therapeutic in the Collagen-induced Arthritis Experimental Model” (doi: 10.1002/art.38272), include Brent Lyda and Theodore M. Kamenecka of TSRI. The Griffin and the Kamenecka labs have a long-standing collaboration to develop novel therapeutics for autoimmune and metabolic disorders. See http://onlinelibrary.wiley.com/doi/10.1002/art.38272/abstract
The work was supported by the National Institutes of Health (grant number MH084512).
About The Scripps Research Institute
The Scripps Research Institute (TSRI) is one of the world’s largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs about 3,000 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists—including three Nobel laureates—work toward their next discoveries. The institute’s graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. For more information, see www.scripps.edu.
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