January 7, 2019
The 2018 Forum for Discovery opened with a series of lectures on new research on the role of our innate immune system in lupus and how discoveries may lead to new therapies.
Roles of the cGAS Pathway in Lupus
Zhijian (James) Chen, PhD, Professor of Molecular Biology at the University of Texas Southwestern Medical Center and an Investigator of Howard Hughes Medical Institute, said that lupus patients commonly have elevated levels of interferons (proteins that signal the presence of pathogens such as viruses, parasites or bacteria) and antibodies which mistakenly attack the body’s healthy cells.
Dr. Chen discovered a new enzyme called cGAS that induces the production of interferons and other molecules that stimulate the immune system and described its pathway, a series of actions that leads to a change in a cell. Dr. Chen’s hypothesis is that disruptions of the cGAS pathway cause the immune system to attack its own tissues and may be a major cause of lupus and other autoimmune diseases. In his lab he is searching for compounds that block cGAS activity that can be developed into effective drugs to treat lupus.
The Cyclic GAMP Pathway in Lupus
Keith Elkon, MD, Professor, Medicine and Head, Division of Rheumatology, University of Washington in Seattle explained how the cGAS-pathway causes cell death, DNA damage, mitochondria damage (mitochrondria are structures located in our cells and are responsible for energy production.) and gene mutations which results in lupus.
He was part of a research team that discovered DNA-activated type interferon pathway, cyclic GMP-AMP synthase (cGAS), was linked to mouse models of lupus. “The cGAS pathway must be tightly controlled to ensure proper immune response against pathogens and to avoid autoimmune diseases,” Dr. Elkon said.
Dr. Elkon also discussed how anti-malarial drugs (AMD) may play a key role in the development of new drugs for systemic lupus that affects the body’s organs and can be life-threatening to a lupus patient. AMDs are effective in the treatment of skin rash and arthritis in lupus. His lab has synthesized a new AMD-like drug called, X6, which is effective on cGAS and more easily tolerated than existing AMD drugs which he is testing in clinical trials in his lab. He is seeking to determine the absorption, distribution, metabolism, and excretion profiles of X6 in mice and then to test X6 in a lupus mouse model to see its effects.