In discovering the DNA sensor cGAS, Zhijian “James” Chen has found the missing link between cytosolic DNA and innate immune activation, paving the way for immunotherapies targeting the cGAS-STING pathway. Although the lowest-hanging fruit has been in immuno-oncology, Chen thinks there are opportunities to target the pathway in a range of autoimmune, infectious, injury and aging-related diseases.
Today, the Foundation for the National Institutes of Health (FNIH) announced Chen is this year's recipient of the Lurie Prize in Biomedical Sciences for identifying cGAS as the linchpin of cytosolic DNA sensing. Chen, a Howard Hughes Medical Institute investigator and professor of molecular biology at University of Texas Southwestern Medical Center, will receive the award at a May 16 ceremony in Washington, D.C.
Although DNA was known to stimulate immune responses, the mechanisms involved eluded researchers for decades. In a 2013 study in Science, Chen and colleagues showed how DNA in the cytosol, a warning sign of viral infection or DNA damage, promotes anti-viral or anti-tumor immunity.
Chen's team showed that upon binding cytosolic DNA, cGAS synthesized ATP and GTP into the cyclic dinucleotide cGAMP. cGAMP bound to and activated STING, which induced secretion of type I interferons.
The discovery catalyzed a flurry of activity, with at least four companies developing STING agonists to crank up innate immunity in cancer. The most advanced is Aduro Biotech Inc.'s STING agonist ADU-S100, which is in Phase I testing to treat lymphoma and solid tumors, and partnered with Novartis AG.
Companies are also exploring the flip-side of the cGAS-STING pathway: both Aduro and Nimbus Therapeutics LLC have preclinical STING antagonist programs for autoimmunity. Separate studies from Pfizer Inc. and academic researchers last year identified small molecule cGAS inhibitors that could help treat autoimmunity.
A series of recent studies from Chen and others suggest sterile inflammation triggered by cytosolic DNA could play a role in a wider array of diseases than previously thought, including myocardial infarction and neurodegenerative diseases.
Chen spoke with BioCentury to discuss the translational applications of the cGAS-STING pathway, and the open questions his team is pursuing.
Edited excerpts from the conversation follow.
"Under some conditions, the cGAS could get exposed to our own DNA, and that's a dangerous situation."
BioCentury:...