A new drug to reduce inflammation in osteoarthritis has shown success in a double-blind study on animal models.
In a study published March 22 in Science Translational Medicine, a research team led by scientists from the University of Southern California (USC) described how their drug R805/CX-011 curbed joint inflammation and other osteoarthritis symptoms in rats and dogs.
“We saw a profound effect on joint pain, structure and function,” Denis Evseenko, M.D., Ph.D., said in a press release. The team is now in the process of launching a clinical trial in collaboration with CarthroniX, a Southern California-based biotech startup co-founded by Evseenko.
Cartilage erosion and inflammation in the joints causes osteoarthritis and leads to stiffness and pain. Osteoarthritis affects more than 32.5 million people in the U.S., a number that’s expected to grow as the average life span increases. Despite its prevalence, there is no cure. Patients are prescribed lifestyle adjustments or physical therapy and may be advised to undergo joint replacement surgery if the condition gets bad enough. Companies have tried to treat osteoarthritis but to no avail so far.
The new drug from the Evseenko lab works by modulating a signaling pathway of an immune receptor called gp130. Among gp130’s vital functions is recruiting immune cells to the sites of infection or injury—including wear and tear on joints. Inflammation here breaks down the tissue even more, perpetuating a vicious cycle that ultimately results in osteoarthritis.
Given that gp130 is essential to several important processes, it can’t be blocked directly. Instead, the Evseenko lab has been working on ways to inhibit its many signaling pathways. Back in 2018, this work resulted in a drug called RGCD 423, which healed damaged joints in rat models. But those benefits weren’t without drawbacks: While it improved symptoms in rats, the drug also inadvertently led to the activation of proto-oncogene Myc, which plays a critical role in cell cycle growth and division. Dysregulated Myc activation has been indicated in cancer development.
R805/CX-011 is an upgraded version of RGCD 423. It works on a different pathway that doesn’t lead to Myc upregulation but does quell the excessive inflammation that is characteristic of osteoarthritis.
To find that pathway, the researchers first homed in on a stretch of amino acids within the gp130 receptor. Previous studies had shown that the section was involved in an immune cell signaling pathway that ultimately led to cartilage degradation. Manipulating the various amino acids there showed that substituting tyrosine for phenylalanine at a specific site could prevent the pathway from being activated, reducing the downstream expression of multiple different types of inflammatory molecules.
After backing up their finding with cell experiments, the lab worked with scientists at USC’s Genome Modification Facility to genetically engineer a mouse model with the tyrosine substitution in the gp130 receptor. Not only were the mice less likely than their wildtype counterparts to develop arthritis, but they also healed and regenerated tissue more readily.
The results led the team to develop R805/CX-011, which works by suppressing activation of the signaling pathway they manipulated in the engineered mouse model. To assess its efficacy in animals, the scientists undertook double-blind studies in rats and dogs, using a setup similar to a clinical trial in humans. The animals’ knees were injected with one of three different doses of the drug then were compared with a control group. R805/CX-011 improved their symptoms in a dose-dependent manner.
The study comes with some limitations. For one, the researchers still need to find out how the signaling cascade that the drug blocks works across different cell types and whether its activity in those cells plays into the outcomes they saw in the models. They also plan to better characterize the different types of inflammatory mediators that are downregulated as a result of mutating the gp130 receptor, which will give insight into how it impacts inflammation.
Meanwhile, the USC team and CarthroniX are in the process of launching a 70-patient phase 1 and 2A clinical trial, which is slated to commence this year. The U.S. Department of Defense will fund the study through grants of more than $5 million, according to USC.
The Evseenko lab is looking at other mechanisms for treating osteoarthritis, too. They published a separate set of study results in January that showed how manipulating another protein, STAT3, could “de-age” joints in mouse models.