STING activation, DNA clearance, and autoimmune disease: investigating pathogenic mechanisms with DNase dysfunction and novel therapeutics in SLE and AGS models 4696

Description Background In healthy individuals, DNase1, DNase1L3, and TREX1 enzymes clear excess chromatin and DNA. Mutations or autoantibodies against these enzymes impair DNA clearance, causing DNA accumulation at inflammatory sites. Systemic lupus erythematosus (SLE) is a leading cause of death among young U.S. women and shares features with type I interferonopathies like Aicardi-Goutières syndrome (AGS), a rare autoimmune disorder marked by neuroinflammation where 30% of cases are due to TREX1 deficiency. Objective: This project investigates the therapeutic potential of a novel DNase biologic in autoimmune diseases resulting from TREX1 deficiency, aiming to advance our understanding of the enzyme’s role in disorders like SLE and AGS. Methods We engineered a long-acting DNase biologic and assessed efficacy in an AGS mouse model (Trex1 knockout, TKO). Survival in treated mice was monitored over 250 days; a smaller cohort underwent mechanistic analysis of immune biomarkers (cytokines, autoantibodies) and molecular pathways. Results DNase biologic-treated mice showed improved survival over controls. Treatment also reduced biomarkers such as dsDNA/MYH6 autoantibodies, CXCL10, and IFN-γ. Untreated TKO mice experienced significant weight loss and myocarditis, which were alleviated in treated mice. Conclusions The DNase biologic showed on-target activity that partially rescued a TKO-driven AGS model, suggesting biologic restoration of DNA clearance may offer a novel approach to treatment. Funding Sources Supported by Colton Center of Autoimmunity Topic Categories Therapeutic Approaches to Autoimmunity (THER)