You may be familiar with the way the cells of our immune system can hunt down germs throughout our body and kill them, but did you know that you have an intricate immune system inside every single one of your cells?
Graphic comparison between a healthy cell and a sick cell. DNA fragments found in the cytoplasm of a sick cell trigger the activation of the STING pathway, which can be aberrantly activated by other conditions such as ALS, LUPUS, SAVI, etc. STING activation requires the presence of a messenger molecule, called gCAMP, that interacts with STING receptor, triggering a cascade of inflammation. Dr. Fitzgerald & Dr. Thompson discovered compound, LB244, can interact with STING receptor blocking this signal and preventing inflammation.
This intracellular immune system is critical for detecting and mitigating the effects of intracellular germs like viruses. For example, the viruses that can cause herpes thrive by injecting their DNA into our cells and tricking our them into using the blueprints found in that viral DNA to make new viruses. Luckily, our cells have their own immune system to defend against these invaders. In healthy cells, DNA is only found in the nucleus or in the mitochondria. However, in a sick virus-infected cell, you can also find viral DNA in the cytoplasm of the cell where it doesn’t belong. The immune system of a cell takes advantage of this abnormality to raise the alarm using a signaling pathway called the STING pathway. When STING senses DNA in places where it doesn’t belong, STING can kick-start other signaling pathways that cause the infected cell to produce inflammatory danger signs to alert other cells to the presence of an infection and to cause the infected cell to die before it can be hijacked to make more virus.
This intracellular immune system is both extremely important and exceptionally strong. Unfortunately, the STING pathway can cause major health problems when it is improperly activated. Improper STING signaling is seen in diseases like amyotrophic lateral sclerosis (ALS), lupus, and other autoimmune diseases like STING associated vasculopathy with onset in infancy (SAVI). There are not currently any drugs approved even for clinical trials in humans. The need for treatments for such terrible diseases inspired scientists, including Dr. Katherine Fitzgerald and our own Dr. Paul Thompson, to work to find new drug candidates to inhibit STING signaling.
It was a stroke of what at first seemed like bad luck that brought Dr. Thompson and Dr. Fitzgerald together. As featured in a previous blog post, Dr. Thompson’s lab primarily focuses on developing inhibitors for the Protein Arginine Deiminases or PADs, enzymes that are overactive in rheumatoid arthritis. Dr. Thompson and his team identified what they thought was a promising PAD enzyme inhibitor that protected mice from developing symptoms of rheumatoid arthritis. However, not only did this inhibitor affect the PADs, the Fitzgerald lab in collaboration with the Thompson lab showed that this compound could also inhibit STING. In fact, this inhibitor blocked STING activity more strongly than it blocked PAD activity! This finding was recently published in the Proceedings of the National Academy of Science.
Even though Dr. Thompson didn’t find exactly what he was originally looking for, Dr. Fitzgerald and he both knew immediately that they’d found something of immense value to the autoimmune disease community. This finding launched a long-term collaboration between the Fitzgerald and Thompson labs to find better STING inhibitors.
This new inhibitor is incredibly promising – it works at very low doses and it effectively inhibits different versions of STING that can be found naturally throughout the human population. So far, the new inhibitor LB244 outperforms all other STING inhibitors in the published literature in every metric Dr. Thompson and Dr. Fitzgerald looked at. Someday soon, this inhibitor and others like it can hopefully be tested to see whether they might be good candidates for clinical trials for diseases like lupus.
This discovery wouldn’t have been possible without a major collaboration between chemists, biochemists, cell biologists, and immunologists. This scientific advance is a paragon of how we are Advancing Cures Together at UMass Chan Medical School and in the Department of Biochemistry & Molecular Biotechnology.
