Exploring RNA targeting therapies as a novel therapeutic option for STING-associated vasculitis with onset in infancy

STING-associated vasculitis with onset in infancy (SAVI) is a rare genetic autoinflammatory disorder caused by heterozygous gain of function mutations in STING1, encoding the Stimulator of interferon genes (STING) protein. Most SAVI patients become symptomatic in infancy with severe vasculitic skin ulceration and the usual cause of death is from severe interstitial lung fibrosis and respiratory failure in the first two decades of life. There is no current effective treatment for SAVI. This project seeks to address this clinical need by exploring antisense oligonucleotides (AONs) as a targeted novel therapeutic option for SAVI.

All clinical features of SAVI are driven by gain of function of the crucial interferon-regulating protein, STING. Gain of function mutations of STING1 associated with SAVI cause abnormal localisation of STING to the Golgi which causes spontaneous protein activation and increased type 1 interferon production, enhanced activation of inflammatory NF-kB pathway, and STING-triggered spontaneous T cell, monocyte, endothelial, and epithelial cell death. We hypothesise that ASOs can be used to modulate STING1 gene expression by targeting STING1 transcripts and thus reverse immune defects associated with SAVI.

The project aims to design and validate AONs to target STING1 mutant transcripts including for the most common heterozygous STING1 mutation (p.V155M) and additional STING1 mutations (N154S, G166E, R281Q, R284G) in SAVI patients. AONs will be designed in collaboration with NATA (Nucleic Acid Therapeutic Accelerator; https://www.natahub.org/) using different chemical modifications - locked nucleic acid (LNA) and 1-methoxyethyl (MOE).