Key result
Screening identifies 57 compounds, including JAK inhibitors, blocking the type I IFN-MHC class I pathway.
Why the study?
Immunosuppressants for autoimmunity are often not curative with many side effects, and therapies are needed targeting the pathogenic type I interferon-MHC class I pathway in myositis.
High throughput screening identified Janus kinase inhibitors and epigenetic/transcriptional modulators as potential therapeutics for idiopathic inflammatory myopathies by inhibiting the type I IFN-MHC class I pathway.
JAK inhibitors merit testing in IIM models; leaves open clinical translation from this animal screening.
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 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.
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Kinder et al. (2020) studied Idiopathic inflammatory myopathies (myositis). Small molecule compound libraries (>4,500 compounds) vs. Vehicle control (DMSO) was evaluated on Inhibition of the type I IFN-MHC class I pathway. High throughput screening of over 4,500 compounds identified 57 active compounds, including JAK inhibitors and epigenetic modulators, that successfully inhibited the type I interferon-MHC class I pathway in human myoblasts.
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