Anti-Inflammatory Effect of miR-197-3p-Loaded Microvesicles in Familial Mediterranean Fever Mouse Model.

Abstract

Familial Mediterranean Fever (FMF) is an inherited autoinflammatory disease triggered by Mediterranean Fever (MEFV) gene mutations that lead to spontaneous pyrin inflammasome activation and exaggerated pro-inflammatory cytokine secretion. The V726A knock-in (KI) mouse model of FMF mimics most of the clinical and immunologic manifestations of the disease, such as recurrent febrile attacks and systemic inflammation. Here, we explored the proof-of-concept evaluation of miR-197-3p-loaded microvesicles (MVs) as a therapeutic approach in the FMF KI mouse model. MVs were purified and structurally characterized through Cryo-Transmission Electron Microscopy (Cryo-TEM), establishing their integrity and size (100-1000 nm), which are compatible for nucleic acid delivery. The miR-197-3p-loaded MVs were retro-orbitally injected in FMF KI mice, and the outcomes were investigated in terms of interleukin-1beta (IL-1β) secretion, CD11b expression in total blood, spleen weight (mg) and back length as a morphological feature. miR-197-3p-loaded MV treatment in Mefvmouse model of FMF decreased the IL-1β level and the expression of CD11b and improved clinical inflammation manifestations. The results show that miR-197-3p-loaded MVs modulate inflammation, as well as improve phenotypic features of FMF, which is a promising, cell-free potential therapeutic strategy for autoinflammatory diseases. This study represents a preliminary proof-of-concept evaluation of miR-197-3p-loaded microvesicles in a murine FMF model, and further long-term and large-scale studies are required before clinical translation can be considered.