Date: Monday, November 8, 2021
Session Title: Abstracts: Innate Immunity (1430–1433)
Session Type: Abstract Session
Session Time: 11:00AM-11:15AM
Background/Purpose: The detection of viral nucleic acids (NA) elicits a transient type I interferon (IFN) response central to antiviral immunity. Chronic type I IFN responses however, driven by the sensing of endogenous NA, can drive severe auto-inflammatory diseases. Indeed in humans, loss-of-function mutations in the intracellular 3’repair exonuclease 1 (TREX1) gene are linked to an accumulation of cytosolic DNA and are associated with type I IFN driven diseases such as Aicardi-Goutières Syndrome (AGS) and systemic lupus erythematosus (SLE). Likewise, TREX1 deficient mice exhibit a chronic systemic interferonopathy. Genetic studies have demonstrated that the cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS) and its downstream adaptor STING, are required to induce the expression of type I IFNs and pro-inflammatory cytokines that are responsible for the auto-inflammatory manifestations of Trex1-/- mice. Pre-clinical validation of cGAS as a small molecule drug target for type I interferonopathies has been elusive due to the lack of a selective cGAS inhibitor with appropriate properties for long term dosing in genetic models.
Methods: We report here that we have developed a novel cGAS inhibitor with favorable pharmacokinetic properties and confirmed that it completely suppresses the type I IFN response to HSV infection.
Results: Using this novel cGAS inhibitor, we have generated the first evidence that selective pharmacological modulation of cGAS activity in a TREX1 deficient mouse model (Trex1em1Aiwsk) can reduce systemic inflammation. A robust reduction in systemic cGAMP, the cGAS product, was observed following two weeks of dosing. As the central clinical presentation in Trex1-/- mice is autoimmune myocarditis, the inflammatory response in the heart was profiled in compound treated mice. Strikingly, reduced cGAMP levels correlated with a down modulation of interferon stimulated gene (ISG) expression, as well as pro-inflammatory cytokine and chemokine expression in the heart. The levels of cytotoxic CD8 and TH1 T cell markers were also reduced, suggesting that cGAS inhibition can impact the adaptive immune response in the context of complex inflammation.
Conclusion: Our novel selective cGAS inhibitor will enable future studies that will deepen our understanding of the role cGAS in Type I IFN driven diseases, and inform therapeutic strategies.
Disclosures: K. Pike, None; A. Caron, None; E. Bérubé, None; R. Beveridge, None; M. Boily, None; J. Burch, None; V. Dumais, None; N. Fradet, None; S. Gaudreault, None; D. McKay, None; M. Raymond, None; E. Seliniotakis, None; D. Sietsema, None; A. Skeldon, None; M. St.-Onge, None; L. Wang, None; M. Crackower, None.
To cite this abstract in AMA style:Pike K, Caron A, Bérubé E, Beveridge R, Boily M, Burch J, Dumais V, Fradet N, Gaudreault S, McKay D, Raymond M, Seliniotakis E, Sietsema D, Skeldon A, St.-Onge M, Wang L, Crackower M. Modulation of Auto-Inflammation with a Novel Selective Cyclic GMP-AMP Synthase (cGAS) Inhibitor in a Trex1-/- Model [abstract]. Arthritis Rheumatol. 2021; 73 (suppl 9). https://acrabstracts.org/abstract/modulation-of-auto-inflammation-with-a-novel-selective-cyclic-gmp-amp-synthase-cgas-inhibitor-in-a-trex1-model/. Accessed May 30, 2023.
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