Researchers have shown that a peptide found only in Old World monkeys—such as macaques and baboons—stopped and even reversed joint disease in a rodent model of rheumatoid arthritis (RA). Results of their novel “retroevolutionary” research were published recently in PLoS ONE.
The peptide, rhesus θ-defensin 1 (RTD-1), is the prototype of a family of small cyclic peptides (θ-defensins) that have a broad spectrum of antimicrobial and immunoregulatory properties. These peptides are found uniquely in Old World monkeys, not in other primates or hominids—including humans.
“Previous studies have shown that RTD-1 modulates lethal inflammation in animal models of infection, and we predicted that RTD-1’s protective mechanism in those models would translate to rheumatoid arthritis, a disease in which chronic inflammation produces irreversible joint damage,” said study author Michael Selsted, MD, PhD, professor and chair of pathology at the University of Southern California’s Keck School of Medicine, Los Angeles, CA.
Complete resolution of RA
For this study, Dr. Selsted and fellow researchers administered a daily subcutaneous dose of RTD-1 to rats with induced arthritis. Control rats with induced arthritis were given saline. Within 24 hours of the first dose, researchers observed reduced arthritis progression in rats treated with RTD-1. By the end of the observation period, treated rats had significantly lower arthritis severity scores (69% reduction of mean) than control animals. Moreover, arthritis completely resolved in 29% of RTD-1-treated rats compared with 2.5% of saline-treated animals.
Limb function and mobility were also restored in RTD-1-treated rats. These rats had markedly reduced erythema and swelling of the affected joints and showed dramatic improvement in function and weight bearing. In further experiments of rats with severe arthritis, those treated with RTD-1 showed comparably dramatic results.
Next, the investigators compared the effects of RTD-1 against the standard first-line arthritis drugs etanercept and methotrexate in other rats with severe arthritis. By day 3 of treatment, both etanercept and methotrexate limited the progression of arthritis. But by day 11, RTD-1 treatment showed a more pronounced effect than either of the other drugs. The RTD-1 treatment also achieved the highest rate of complete disease resolution (25%) compared with methotrexate (4.5%) or etanercept (0%).
“Our findings strongly suggest that RTD-1 has potential as a completely new agent for treating rheumatoid arthritis,” said Dr. Selsted. “RTD-1-like molecules may also be effective in the treatment of other inflammatory diseases and cancer.”
So, if Old World monkeys make their own θ-defensins, does that mean they never develop arthritis?
“I asked this very question to a colleague who runs one of the largest primate centers in the world, and he told me that RA-like disease is not seen in any of the Old World species he has observed for decades,” Dr. Selsted said.
“Moreover, rhesus monkeys are more than a thousand times more resistant [than humans] to endotoxemia—the fever and systemic reaction induced when bacteria such as E. coli gets into our circulation,” he added. “Baboons are so resistant to bacterial infection that they are hardly used now to study human endotoxemia and sepsis. We are quite confident that θ-defensins and engineered analogs will find numerous applications in human medicine.”
The researchers are now conducting toxicology studies of RTD-1 in animals. They anticipate trials of RTD-1 in humans in the first half of 2018.
Dr. Selsted and other authors of this study have patented synthesized θ-defensins, and have started a company, Oryn Therapeutics, to develop these drugs for treatment of autoimmune and inflammatory diseases.