Graduate Student Yale University New Haven, Connecticut, United States
Introduction/Rationale: Aicardi–Goutières syndrome (AGS) is an early onset progressive encephalopathy induced by biallelic pathogenic variants in genes responsible for degrading or sensing cytoplasmic nucleic acids. AGS exhibits phenotypic overlap with Systemic lupus erythematosus (SLE) in that both are type 1 interferonopathies, but AGS may additionally induce microcephaly, seizures, developmental delays, and significant mortality in infants. Approximately 30% of AGS cases are due to TREX1 deficiency. To investigate the role of extracellular nucleic acid signaling in the pathogenesis of AGS we examined the effects of a long acting DNase biologic with dual DNAse1/DNAse1L3 activity (called 1687) on the survival and cytokine profiles of Trex1-/- mice.
Methods: We treated Trex1-/- mice weekly with vehicle or subcutaneous injections of 1687 at 1 mg/Kg, and monitored survival for 250 days. A smaller cohort underwent mechanistic analysis of immune biomarkers (cytokines, autoantibodies) and molecular pathways.
Results: Vehicle treated Trex1-/- mice succumbed to disease as early as five weeks of age with a median survival of 98.5 days, while mortality in the Trex1-/- treated mice began around 10 weeks of age and did not reach a median survival within the 250-day window. At 250 days approximately 80% of the vehicle treated Trex1-/- mice had expired, compared with approximately 45% of the 1687 treated Trex1-/- mice. Treated mice displayed reductions in extracellular inflammatory cytokines along with reduced anti-dsDNA and MYH6 auto-antibodies. However, no differences in cytokines induced by the intracellular cGAS–STING pathway were observed in treated and untreated animals.
Conclusion: Our findings document a pathogenic role for extracellular DNA signaling in AGS, a disease whose accepted pathogenic mechanism is defective intracellular nucleic acid signaling. Our results further suggest that extracellular DNA clearance may offer a therapeutic benefit to AGS patients.
