What Can RNA Therapies Offer for Rheumatology?

Beyond the well-known mRNA vaccines for COVID-19, therapeutic RNAs are emerging in diverse medical fields, including cardiology, ophthalmology, infectious diseases, and hepatology. However, could they also hold promise in rheumatology?

During a session at the recent French Congress of Rheumatology (SFR 2024) in Paris, France, Florence Apparailly, PhD, from the Centre Hospitalier Universitaire de Montpellier, Montpellier, France, affirmed their potential, describing these small genetic molecules as “a promising solution in rheumatology.”

RNA therapies offer the key advantage of precisely targeting genes or proteins involved in the inflammatory and autoimmune pathways. This specificity could enable personalized treatments while minimizing the side effects often seen with conventional therapies that act more broadly.

Apparailly focused on advances in rheumatology research on small noncoding RNAs during her presentation. “Their big advantage is that it is possible to synthesize any sequence in very large quantities, in a short time and for a much more competitive price than traditional small molecules,” she said.

Preclinical Progress

Antisense oligonucleotides have been evaluated in rheumatoid arthritis (RA) and systemic lupus erythematosus to modulate the immune system activity and reduce the inflammatory response.

In RA, these small RNAs have been designed to block proinflammatory cytokine levels, such as tumor necrosis factor, interleukin 6, and other inflammatory mediators.

A study in mouse models of systemic lupus erythematosus with renal involvement showed that repeated subcutaneous injections of an antisense oligonucleotide targeting complement factor B, an activator of the alternative complement pathway, reduced plasma factor B levels, lowered kidney damage, and improved survival.

Another study revealed that inhibiting the Gαq/11 protein using an antisense oligonucleotide in a mouse model of lupus reduced inflammation and alleviated lupus symptoms.

“Although these applications are still in the research phase, they represent a promising area for new targeted therapies in treating rheumatic diseases,” Apparailly emphasized.

Interfering RNA (RNAi)

RNAi, which inhibits the production of pathogenic proteins by stopping translation or degrading target mRNA, has also been tested in inflammatory rheumatism.

In a preclinical mouse model of RA, RNAi was shown to reduce synovitis, bone erosion, and other clinical symptoms.

Additionally, introducing small RNAi inhibiting genes regulating inflammation in monocytes improved the outcomes of experimental arthritis in mice.

Delivery Challenges

A major hurdle for RNAi is ensuring efficient delivery to target cells. Therefore, researchers have worked on innovative vectors, such as cationic liposomes and viral vectors, to transport RNAi directly into circulating monocytes that cause chronic inflammation during inflammatory flare-ups. This strategy has improved therapeutic efficacy.

“We were able to provide extensive in vivo proof of concept that RNAi delivery to blood monocytes represents a strategy of choice for the treatment of RA. I am convinced that RNAi will play a central role in the management of chronic inflammatory diseases in the future,” she concluded.

This story was translated from Medscape’s French edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.