W194 - Modulation of Chronic EAE and by Oral Administration of miR-30d

Abstract Text:

Background: Fecal microRNAs are an emerging therapeutic area and may act either by direct modulation of the immune system by modulating the microbiome. We found that fecal microRNAs shape the microbiome,1 that miR-30d is elevated in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE),2 and that oral gavage of miR-30d ameliorates acute EAE, increases Tregs, and expanding Akkermansia muciniphila.2 In this study, we investigated the effects of miR-30d in the chronic animal models of MS and immunologic changes in the CNS.
Materials and methods: miR-30d was tested in the acute C57BL6 MOG EAE model and the progressive PLP/SJL adoptive transfer model, which develops cortical lesions, leptomeningeal inflammation and other features shared with progressive MS. EAE was induced and mice were orally gavaged with different concentrations of miR-30d or scramble miR after disease onset. PLP polarized splenocytes were cultured with either miR-30d or scramble and MHC II expression was analyzed with FLOW.

Results: 0.3625mg of miR-30d significantly reduced EAE severity in both acute and progressive EAE models. This effect was mediated through the downregulation of MHCII expression in microglia, brain-infiltrating monocytes, and neutrophils. Furthermore, when PLP-polarized splenocytes were cultured with PLP and miR-30d or scramble, miR-30d also downregulated MHCII expression in monocytes and neutrophils in vitro. This suggests that miR-30d directly modulates MHCII expression in myeloid cells.

Discussion: Oral miR-30d treatment ameliorates EAE by downregulating MHC II and affecting microglia and monocytes, important components of progressive MS. GMP MiR-30d is being manufactured for phase 1 testing in healthy volunteers.