Development of siRNAs targeting interferon beta as a novel therapeutic approach for adult and juvenile dermatomyositis

Initial screening of 27 siRNAs identified two lead siRNAs with significant knockdown of both IFN beta transcript and secreted protein in all cell lines, with one lead siRNA demonstrating a more favourable cytotoxicity profile. RNA sequencing and pathway analysis revealed that both lead siRNAs were able to reduce the induction of viral, immune and autoimmune pathways in dermal fibroblasts and JDM myotubes. An additional 47 siRNAs across the IFNB1 locus were screened; however, the previous lead siRNA remained the most active across relevant cell lines.

Comprehensive in vitro screening identified a lead siRNA targeting IFNB1 with significant mRNA and protein knockdown activity, low cytotoxicity and the ability to modulate immune-relevant pathways in muscle and skin cells. This is a promising first step towards the development of an siRNA therapy for DM/JDM and other conditions driven by IFN beta over-expression.