Development of siRNAs targeting interferon beta as a novel therapeutic approach for adult and juvenile dermatomyositis
- 1Medical Research Council Nucleic Acid Therapy Accelerator (NATA), Research Complex at Harwell , ,
Abstract
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.
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BibTeX
@article{parkes2026development,
title = {{Development of siRNAs targeting interferon beta as a novel therapeutic approach for adult and juvenile dermatomyositis}},
author = {Joanna E. Parkes and Andrés F. Correa-Sánchez and Inês Fial and Isaac Tam and Kaladevi Selvam and Mark Cunningham and Nick Lench and Peter L. Oliver},
journal = {Frontiers in immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1851483},
url = {https://europepmc.org/article/PMC/PMC13668828},
note = {CC BY},
}
RIS
TY - JOUR
TI - Development of siRNAs targeting interferon beta as a novel therapeutic approach for adult and juvenile dermatomyositis
AU - Joanna E. Parkes
AU - Andrés F. Correa-Sánchez
AU - Inês Fial
AU - Isaac Tam
AU - Kaladevi Selvam
AU - Mark Cunningham
AU - Nick Lench
AU - Peter L. Oliver
PY - 2026
DA - 2026/10/01
JO - Frontiers in immunology
DO - 10.3389/fimmu.2026.1851483
UR - https://europepmc.org/article/PMC/PMC13668828
AB - 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.
SN - 1664-3224
ER -