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. The detection of DNA plays an important 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 generation 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 binds 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 cGAS-STING pathway’s ability to mediate immune responses that would otherwise lead to cancer, autoimmune diseases and infection.
Given its role in innate immunity, leveraging the cGAS-STING pathway presents significant opportunities for treating a host of diseases:
Stimulating pathway upregulation with agonists to elicit an immune response and assist the host in battling the disease
Inhibiting or downregulating the pathway when aberrant autoimmunity results in undesired inflammation and medical conditions
The cGAS-STING pathway is a promising target for cancer immunotherapy. By detecting tumor-derived DNA, cGAS can stimulate endogenous antitumor immunity. In preclinical studies, the cGAS-STING pathway has demonstrated that it is essential for type I IFN production (inflammatory proteins) in tumors, as well as its ability to generate antitumor immune responses.
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 normal cells. There are more than 80 types of autoimmune diseases that affect a wide range of body parts.
Preventing aberrant activation of the cGAS-STING pathway is crucial for maintaining immune homeostasis. If the cGAS-STING pathway is unreasonably activated by lack of regulation, it causes activation of the immune system, resulting in autoimmune diseases.
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.
The rise of immunotherapies that stimulate the host immune system has unlocked new opportunities in cancer therapy. Immune checkpoint blockade therapy with neutralizing antibodies blocking T-cell inhibitor molecules such as CTLA-4, PD-1 and PD-L1, has shown remarkable clinical effects, but on average, only about 20% of patients respond to these inhibitors depending on the tumor type and stage of disease. Antitumor activity within these non-responding patients is insufficient to mount a robust immune response, i.e. the patient tumor is “cold.” Hence, a major focus of current immunotherapy research is to augment innate immunity and foster a T-cell rich tumor environment to turn “cold” tumors “hot.”
To date, investigational therapies utilizing the cGAS-STING pathway has focused on activating the immune system through STING agonism. There is a growing body of evidence supporting the use of STING agonist in combination with immunotherapy like checkpoint inhibitors and non-immunotherapy such as radiation and chemotherapy. IMSA101 – our lead program designed to activate STING with high specificity – is currently in Phase 2 development in combination with immunotherapeutic drugs and non-immunotherapy approaches.
We are also developing a technology platform to create immune stimulatory drug conjugates to deliver STING agonists to target tumors. Leveraging our expertise in the cGAS-STING pathway, we are investigating the optimal combination of therapies and clinical settings in which to develop our STING agonist programs.
ImmuneSensor is actively evaluating small molecule cGAS inhibitors as a potential treatment for diseases and conditions caused by aberrant activation of the cGAS-STING pathway including:
Aicardi-Goutieres syndrome (AGS)
COPA syndrome
Systemic lupus erythematosus
Rheumatoid arthritis
Parkinson disease
Huntington disease
Amyotrophic lateral sclerosis and frontotemporal dementia (FTD)
Age-dependent macular degeneration
Nonalcoholic steatohepatitis
Acute pancreatitis