Validating interferon score and phospho-STING level as disease biomarkers of COPA syndrome - PROJECT SUMMARY: COPA syndrome is a rare inborn error of immunity considered a monogenic interferonopathy. It is caused by autosomal dominant missense mutations in the coatomer subunit alpha (COPA) gene. The most common clinical manifestations are interstitial lung disease (ILD), arthritis, and kidney disease. Despite best-available treatment, COPA syndrome remains a highly morbid disease and patients can develop debilitating arthritis, renal failure and end stage pulmonary fibrosis. Some patients require lung or kidney transplantation. Thus, there is a critical need to identify and develop new treatments for COPA syndrome. We have the largest clinical and research cohort of COPA syndrome patients in the world. We built this cohort through our NIH-funded translational research in COPA syndrome and involvement with the COPA Syndrome Foundation. This work began when our centers collaborated in the discovery of the disease in 2015. The goal of this proposal is to validate the peripheral blood interferon (IFN) score and phosphorylated STING (pSTING) level as disease biomarkers of COPA syndrome in anticipation of clinical trials. We and others have shown that COPA syndrome is caused by abnormal accumulation, activation and phosphorylation of STING on the Golgi, which leads to chronic interferon signaling. However, it remains unknown whether pSTING levels or IFN scores dynamically change during the course of disease or in response to treatment. In this proposal, we hypothesize that peripheral blood mononuclear cell (PBMC) pSTING levels and IFN scores are biomarkers that correlate with disease severity and activity of COPA syndrome. We will collect serial samples from patients with COPA syndrome to test this hypothesis by 1) establishing the range of IFN scores in COPA syndrome and correlate these with disease phenotype, severity and activity using validated clinical outcome assessment measures and 2) determining how pSTING levels measured by multi-color flow cytometry correlates with disease activity, treatment and severity in COPA syndrome and establish the range of normal pSTING levels in healthy controls. Through our work we will perform the first and largest comprehensive natural history study of COPA syndrome and provide the first description of IFN scores in this disease. We will also establish normal values for pSTING in healthy control PBMCs using flow cytometry and report levels observed in COPA syndrome. By correlating serial data for IFN score and pSTING with scores from clinical outcome assessment measures, we will establish whether IFN scores and pSTING can serve as predictive, monitoring or response biomarkers in COPA syndrome. These results will be critical to informing future clinical trial design and implementation for COPA syndrome as we work to identify targeted therapeutics for these rare patients.
