Leveraging the cGAS-STING Pathway
The innate immunity system is comprised of many pathways, molecules and cells that detect and respond to external and internal stimuli. One of the key pathways is the cGAS-STING pathway, which works to detect both foreign and host-derived DNA in the cytosol, a compartment where DNA does not reside in healthy cells. The detection—known as sensing—of DNA serves an essential role in the immunity of many organisms, and in mammalian cells, has evolved to incite a complex immune cascade that works to protect the body.
The process begins when the cyclic GMP-AMP synthase (cGAS) enzyme detects DNA that has leaked into the cytosol due to genome instability or cellular damage. As cytosolic DNA can originate from multiple sources, the cGAS-STING pathway is implicated in autoimmune diseases, infection, senescence and cancer.
Once the immune system becomes activated through the cGAS-STING pathway, the double-stranded DNA binds to cGAS, which is followed by the synthesis of cGAMP from ATP and GTP. cGAMP functions as a secondary messenger that binds to stimulator of interferon gene (STING). This triggers phosphorylation of IRF3 via TBK1 and expression of type-1 interferon (IFN). Next, type-1 IFNs bind to type-1 IFN receptors, which activate a signaling cascade that leads to the expression of hundreds of IFN-stimulated genes (ISGs) and inflammatory cytokines.
The release of these cytokines results in an innate immune response and activation of adaptive immunity, highlighting the central role of the cGAS-STING pathway in mediating immune responses that can result in inflammatory or autoimmune disorders or elicit immunity against cancer or microbial infection.
Therapeutic Applications
Modulators of the cGAS-STING Pathway
Given its role in innate immunity, leveraging the cGAS-STING pathway presents significant opportunities for treating a host of diseases. ImmuneSensor is currently focused on developing cGAS inhibitors that have the potential to address a broad range of inflammatory and autoimmune diseases.
Autoimmune Diseases
Autoimmune disease arises when the body’s natural defense system cannot distinguish between its own cells and foreign cells, resulting in the body mistakenly attacking healthy cells. There are more than 80 types of autoimmune diseases that affect a wide range of tissues. Preventing aberrant activation of the cGAS-STING pathway is crucial for maintaining immune homeostasis. When the cGAS-STING pathway is inappropriately activated by lack of regulation, it causes activation of the immune system, resulting in inflammation and autoimmunity. Inhibiting or downregulating the pathway when aberrant autoimmunity results in undesired inflammation and medical conditions due to the chronic uncontrolled activity of cGAS
Several enzymes (RNase H2, TREX1, and DNase II) regulate cGAS activation by controlling the basal level of cytosolic DNA. Mice deficient in these functional enzymes have been shown to develop autoimmune disease with inflammation and lethality in a cGAS- and STING-dependent manner, suggesting a critical role for the cGAS-STING pathway in the pathogenesis of autoimmune diseases.
ImmuneSensor is developing small molecule cGAS inhibitors as a potential treatment for diseases and conditions caused by aberrant activation of the cGAS-STING pathway including:
MONOGENIC AUTOINFLAMMATORY SYNDROMES
Aicardi-Goutières syndrome (AGS)
COPA syndrome
AUTOIMMUNE DISEASES
Systemic lupus erythematosus
Cutaneous lupus erythematosus
Dermatomyositis
Rheumatoid arthritis
METABOLIC DISEASES
Nonalcoholic steatohepatitis
Acute pancreatitis
Kidney Diseases
CARDIOVASCULAR DISEASES
Myocardial infarction
Chronic heart failure
SENESCENCE, AGING AND NEUROLOGICAL DISORDERS
Alzheimer’s disease
Parkinson’s disease
Huntington’s disease
Amyotrophic lateral sclerosis and frontotemporal dementia (FTD)
Charcot Marie Tooth syndrome
Age-dependent macular degeneration
In 2024, ImmuneSensor initiated human clinical trials in healthy volunteers of its potential best-in-class orally available small molecule cGAS inhibitor known as IMSB301. In preclinical models, IMSB301 rescued development of mortal inflammatory diseases in genetically engineered mouse models in which the cGAS-STING pathway is chronically activated. In addition, IMSB301 was shown to provide significant therapeutic benefit in mouse models of inflammatory arthritis.
Partnership opportunities
We have deep experience in developing small molecules to modulate the cGAS-STING pathway for various therapeutic applications and are interested in discussing collaboration opportunities with potential partners. If you would like to learn more, please contact us at BD@Immunesensor.com.