Evolutionary Backtrack Offers Up Novel Rheumatoid Arthritis Candidate

A peptide found exclusively in Old World monkeys has been shown to completely reverse joint disease in a rat model of rheumatoid arthritis (RA), and could represent a new form of “retroevolutionary’” therapy for RA in humans, according to researchers in the U.S. The peptide, known as rhesus θ-defensin 1 (RTD-1), is the prototype of a family of small cyclic θ-defensins, which are the only circular proteins found in animals.

Studies headed by Michael Selsted, M.D., Ph.D., chair and professor of pathology at the Keck School of Medicine, University of Southern California, found that RTD-1 was more effective than either of the current gold standard treatments methotrexate or etanercept at treating a severe form of induced RA in rats. “Our findings strongly suggest that RTD-1 has potential as a completely new agent for treating rheumatoid arthritis,” Selsted claims. “RTD-1-like molecules may also be effective in the treatment of other inflammatory diseases and cancer.”

The researchers report their findings in PLOS ONE, in a paper entitled “Suppression and Resolution of Autoimmune Arthritis by Rhesus θ-Defensin-1, an Immunomodulatory Macrocyclic Peptide.”

Defensins are a group of host defense peptides that comprise three evolutionarily related structural families, α-, β-, and θ-defensins, the researchers explain. Most mammals express α- and β-defensins, whereas θ-defensins are unique to Old World monkeys. Studies have already demonstrated that θ-defensins possess broad-spectrum antimicrobial activities and immunoregulatory properties, and have shown that RTD-1 suppresses proinflammatory cytokines and can prevent death in mouse models of severe infection. As Dr. Selsted notes, with this evidence to hand, the team “predicted that RTD-1’s protective mechanism in those models would translate to RA, a disease in which chronic inflammation produces irreversible joint damage.”

The team investigated the effects of RTD-1 in rats with pristane-induced arthritis (PIA), a model of RA that shares many features of the human disease. Animals were injected with either RTD-1 or saline for 11 days. Beneficial results were seen almost straight away. Improvements in the 31 RTD-1–treated animals were evident within just 24 hours of starting therapy. And by the end of the observation period, the animals’ joints were free from swelling and other features of disease and their limb function and mobility was restored.

“RTD-1 treatment markedly reduced erythema and swelling of the affected joints and dramatic improvement in function and weight bearing,” the authors write. “The clinical improvement in RTD-1-treated rats correlated with preservation of normal joint histology that was similar to limbs of naïve animals, as joints from peptide-treated animals were devoid of synovial hyperplasia, inflammatory infiltration, angiogenesis, and erosive changes preserving a normal architecture.” Complete resolution of disease was seen in 29% of the group treated with RTD-1.

The effects of RTD-1 on advanced PIA disease were just as dramatic. RTD-1 treatment of animals with near-maximal disease resulted in rapid reductions in arthritis severity, with complete resolution of clinical disease in all the RTD-1–treated rats by day 15. “As with animals treated in early PIA, RTD-1 treatment of animals with severe PIA restored normal limb function and mobility,” the researchers report.

In a comparative study in the PIA rats, the authors showed that RTD-1 therapy was more effective than treatment with either methotrexate or the anti-tumor necrosis factor (anti-TNF) biologic drug etanercept. Although both of the marketed RA drugs limited progression of arthritis in treated animals by day 3 of therapy, treatment with RTD-1 had a far more pronounced effect by day 11. The rate of complete disease resolution was 25% with RTD-1 therapy, much higher than that achieved with methotrexate therapy (4.5%) or etanercept (0%).

The beneficial effects of treatment with RTD-1 were dose-dependent, and therapy was effective even when administered only once every five days. Encouragingly, RTD-1 was also nonimmunogenic, negating the likelihood that treatment will trigger neutralizing antibodies, which is a problem for some patients treated using biologics, the researches point out. Their further analyses of tissues in treated and control rats confirmed that RTD-1 dose-dependently reduced joint levels of the cytokine interleukin-1β (IL-1β), inhibited fibrolast-like synoviocyte (FLS) invasiveness and FLS IL-6 production, blocked arthritogenic proteases that activate TNFα, and inhibited matrix metalloproteases and cathepsin K.

“The results of this study indicate that θ-defensin-like cyclic peptides have potential as new agents for treatment of RA,” the authors conclude. “The concept of using a nonhuman primate peptide represents a novel retroevolutionary therapeutic paradigm whereby products of genes expressed in Old World monkeys may be used to treat a human autoimmune disorder.”