Vanderbilt biomedical engineers have demonstrated the potential for the first clinically available osteoarthritis drug that interrupts the disease process rather than solely managing the pain it causes.
The group used “packages” of engineered nanoparticles to sustainably deliver a type of RNA to the cells in the joint over time after treatment. With this technique, a single injection lasted for at least a month and reduced cartilage loss and bone spurs—known to be primary drivers of severe joint pain that ultimately causes patients to seek complete joint replacement.
Cornelius Vanderbilt Professor of Engineering Craig Duvall and his team set out to develop a drug for the prevention of post-traumatic osteoarthritis initiation and progression. PTOA, caused by degraded cartilage that cushions the ends of bones in joints, and is most seen among young athletes and military personnel. ACL rupture, meniscus tear, patellar dislocation, and ankle instability are among the precursors to PTOA.
The disease leads to earlier onset and faster progression of osteoarthritis following an injury, an accelerated process that benefits research into potential treatments.
The same degenerative mechanisms are in play in PTOA and age-related osteoarthritis, which affects 25 percent of those over 45 in the U.S. MMP13, a protein coding gene, is responsible for degrading cartilage. But researchers have yet to develop a therapy to inhibit the progression that doesn’t have adverse side effects.
Traditional drug development approaches have struggled to discover small molecule inhibitors that selectively target MMP13, which is problematic because inhibiting the broader class of similar enzymes can cause side effects and/or toxicities. Additionally, previously tested MMP inhibitors have been delivered systemically, meaning potential activity and side effects in all tissues of the body.
Instead, the research team, which includes former graduate student Sean Bedingfield, PhD ‘20, and current graduate student Juan Colazo, developed short interfering RNA-based drugs known as siRNAs. A nanoparticle loaded with the MMP13 siRNA is locally injected and binds only to damaged cartilage affected by joint injuries. The targeted, bioadhesive nanoparticle stays in the joint longer to better combat early cartilage damage, and the method also helps to further reduce potential undesirable effects elsewhere in the body, said Duval, professor of biomedical engineering.
Current treatments like corticosteroid joint injections manage short term pain, but they may worsen cartilage loss when used as an ongoing therapy, he said.
“Direct comparisons to treatment with the current clinical standard—steroids—showed that MMP13 silencing with the targeted nanoparticles had significant effects on reducing joint degeneration over steroid injections,” Duvall said. “This indicates that this approach has the potential to be developed as the first clinically available disease modifying osteoarthritis drug.”
The team and its collaborators hope to continue to explore bio-adhesive nanoparticles that are easier to scale and last longer. “We’d also like to show safety and efficacy in larger models as a steppingstone toward longer term application of MMP13 siRNA therapies in patients,” he said.
“Amelioration of post-traumatic osteoarthritis via nanoparticle depots delivering small interfering RNA to damaged cartilage” was published in the journal Nature Biomedical Engineering in August 2021. The same month, the journal ACS Nano published a follow up paper, “Top-Down Fabricated Microplates for Prolonged, Intra-articular Matrix Metalloproteinase 13 siRNA Nanocarrier Delivery to Reduce Post-traumatic Osteoarthritis.”
The work was supported by the Department of Defense Peer Reviewed Orthopaedic Research Program, the National Institutes of Health, the Canadian Natural Sciences and Engineering Research Council, the Rheumatology Research Foundation, a VA Merit Award, the National Science Foundation Graduate Research Fellowship Program, the European Research Council and the European Union’s Horizon 2020 Research and Innovation Programme.