Muzzling a key enzyme that triggers an alarm used to activate our immune systems could play a role in preventing at least two autoimmune diseases.
Building on work that dates back at least three years, investigators at UT Southwestern say that inhibiting the cGAS enzyme sets off an inflammatory cascade that causes the autoimmune effect when self-DNA is "inappropriately" contained in the cytoplasm. Their work was published in the Proceedings of the National Academy of Sciences.
The absence of the TREX1 protein, which digests DNA, has been linked to autoimmune disease. But when the investigators inhibited cGAS in mice, they found that they could prevent the two autoimmune diseases from occurring in the rodents.
Now they're working on high-res structures of cGAS to pursue the identification of small molecules that could best do the work of blocking the enzyme.
"These results suggest that inhibition of the enzyme cGAS may be an effective therapy for autoimmune diseases such as Aicardi-Goutieres Syndrome and systemic lupus erythematosus, which are linked to the same inflammatory pathway," said senior author Dr. Zhijian "James" Chen, a professor of molecular biology and a Howard Hughes Medical Institute investigator at UT Southwestern.
"Even deletion of just one of the two genes for cGAS largely rescued the mice from the autoimmune disease," said Dr. Chen, who is also an investigator in the Center for the Genetics of Host Defense and holder of the George L. MacGregor Distinguished Chair in Biomedical Science.
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