RNA interference (RNAi) is one of the most exciting and important discoveries of the past few decades. Small interfering RNAs (siRNAs) can silence gene activity and be used to interfere with pathophysiological processes. Substantial research has focused on introducing 'drug-like' properties to RNAi molecules, and clinical trials have been initiated. Despite initial success, the current challenge that remains is to develop vehicles that efficiently deliver the therapeutic siRNA to specific cell types.
As for many other diseases, siRNA-based therapy is also emerging as a promising approach for the treatment of rheumatoid arthritis (RA). Although the pathogenesis of RA is complex, identification of candidate genes able to influence inflammatory response has been successful. As for the cell population to target for RNAi-mediated anti-inflammatory intervention in RA, monocytes display optimal features. Indeed, due to their capacity to differentiate into dendritic cells (DC), M1/M2 macrophages as well as osteoclasts (OC), monocytes control both inflammation and bone turnover, two hallmarks of RA. There are however functionally distinct subsets of monocytes that control homeostatic and inflammatory processes. Excessive and prolonged activation of monocytes – and especially Ly6Chigh “inflammatory” monocytes in the mouse – is a hallmark of chronic inflammation. Precise targeting of this cell subset could be therapeutically beneficial while sparing other subsets and leukocytes.
We will present strategies developed to target Ly6Chigh monocytes with optimized lipid-based formulations as well as therapeutic siRNAs used to silence inflammation in mouse. We will also discuss potential applications of siRNA therapeutics in clinical trials for RA.
Disclosure of Interest None declared