Immunosuppressants used to treat autoimmunity are often not curative and have many side effects. Our purpose was to identify therapeutics for autoimmunity of the skeletal muscle termed idiopathic inflammatory myopathies (myositis). Recent evidence shows the pro-inflammatory type I interferons (IFN) and a down-stream product major histocompatibility complex (MHC) class I are pathogenic in myositis. We conducted quantitative high throughput screening on >4,500 compound titrations through a series

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... of cell-based assays to identify those that inhibit the type I IFN-MHC class I pathway in muscle precursor cells (myoblasts). The primary screen utilized CRISPR/Cas9 genome-engineered human myoblast containing a pro-luminescent reporter HiBit fused to the C-terminus of endogenous MHC class I. Active compounds were counter-screened for cytotoxicity and validated by MHC class I immunofluorescence, Western blot, and RT-qPCR. Actives included Janus kinase inhibitors and epigenetic/transcriptional modulators. Testing in animal models and clinical trials is warranted to translate these therapies to myositis patients.