Oklahoma ACE: Molecular Destruction of Autoimmune Disease to Aid Clinical Trail Success

Project Summary The Oklahoma ACE (OACE) aims to understand autoimmune disease biology through interdisciplinary, collaborative research integrating clinical and basic questions. Prior OACE work as both a Basic and Clinical ACE has significantly advanced our understanding of autoimmune disease genetics, development, flare, and heterogeneity. The OACE has also contributed to eight ACE trials, serving as a Protocol Chair and/or a lead recruitment site for five while also building unique patient cohorts and data/sample collections from diverse urban, rural, and minority communities. Through this UM1 Clinical ACE submission, the OACE strives to deconstruct the molecular heterogeneity of autoimmune disease to implement more effective clinical trial designs, optimize biologically relevant treatment selection, and improve disease understanding. Our primary clinical project builds on our extensive prior work demonstrating a role for EBV reactivation in SLE disease transition, disease activity, and activation of interferon pathways. Utilizing our innovative SLE trial design that provides temporary steroids to allow background immunosuppressants withdrawal, we will test the effectiveness of EBV vaccination in suppressing disease activity and interferon responses in biomarker- selected SLE patients. Partnered mechanistic studies will test the impact of EBV reactivation on autoantibody production and B cell and monocyte activation and function in patients. Preliminary data in our alternate clinical project has found a critical role of the type I IFN pathway in neuromyelitis optica, a complex autoimmune disease with up to 40% of patients have continual relapse and damage even with standard-of- care treatment. We have found that high type I IFN signatures are associated with irreversible disability after an NMO relapse and increased B and Th17 cell signature activation. This first-in-NMO study will assess the effectiveness and safety of the type I IFN receptor antagonist anifrolumab in NMO. Mechanistic studies will determine changes in type I IFN, B cell, and Th17 responses and autoantibody production. Our collaborative project deconstructs molecular heterogeneity and associated pathogenic mechanisms of SLE. Building on preliminary data using multi-omic machine learning to predict abatacept treatment response at baseline, we will distinguish determinants of belimumab treatment in SLE patients initially using deep immunophenotyping, epigenetics, and transcriptomics, evolving to include single-cell technologies as necessary, to capture the biology that determines treatment response. New with this renewal, we propose our OMRF CAP-certified Biorepository to serve as the ACE Biorepository Core, leveraging decades of experience as an autoimmune disease biorepository, dedicated personnel, standard policies/procedures, and high biobanking standards. Our Administrative Core will support an Autoimmune Disease Enrichment Program and Scholars Program and assist with these clinical and collaborative projects. The OACE will also continue to recruit for ACE Network trials and collaborate with other ACE Centers to advance scientific discoveries that improve patient lives.