Frontiers in immunology · 2026
Development of siRNAs targeting interferon beta as a novel therapeutic approach for adult and juvenile dermatomyositis.
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Parkes Joanna E, Correa-Sánchez Andrés F, Fial Inês, Tam Isaac, Selvam Kaladevi, Cunningham Mark, Lench Nick, Oliver Peter L
Аннотация
BACKGROUND: A key feature of the autoimmune conditions adult and juvenile dermatomyositis (DM/JDM) is the correlation of interferon (IFN) beta induction with disease initiation and activity. Our aim was to establish a short interfering RNA (siRNA) approach to knockdown IFNB1 expression as a therapeutic strategy for DM/JDM.
METHODS: A library of 74 siRNAs targeting IFNB1 was designed and screened for IFNB1 knockdown by qRT-PCR. Lead siRNAs were analysed for secreted IFN beta protein reduction and acute cytotoxicity. IFNB1 expression was induced for efficacy screening in vitro, including in immortalised myoblasts, myotubes and dermal fibroblasts, alongside JDM patient-derived myotubes. RNA sequencing was also performed on siRNA treated and untreated dermal fibroblasts and patient myotubes.
RESULTS: 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 disease-associated 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.
CONCLUSIONS: Overall, 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.
METHODS: A library of 74 siRNAs targeting IFNB1 was designed and screened for IFNB1 knockdown by qRT-PCR. Lead siRNAs were analysed for secreted IFN beta protein reduction and acute cytotoxicity. IFNB1 expression was induced for efficacy screening in vitro, including in immortalised myoblasts, myotubes and dermal fibroblasts, alongside JDM patient-derived myotubes. RNA sequencing was also performed on siRNA treated and untreated dermal fibroblasts and patient myotubes.
RESULTS: 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 disease-associated 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.
CONCLUSIONS: Overall, 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.