BellBrook Labs has been awarded a $1.8 million Phase II SBIR grant by the National Institute of Allergy and Infectious Diseases (NIAID) to develop lead molecules that block cyclic GAMP synthase (cGAS) for the treatment of lupus and other autoimmune diseases. BellBrook’s CEO, Dr. Robert Lowery is the principal investigator for the effort, and Dr. Keith Elkon, Head of Rheumatology at the University of Washington, Seattle, is a collaborator.
Lupus is the second most common autoimmune disease, affecting more than 300,000 people in U.S, with 16,000 new cases annually. Lupus patients suffer from various symptoms, including skin lesions, arthritis, and fatigue; it strikes women much more frequently than men. Though the disease can be mild, lupus causes major organ damage in 50% of cases; e.g., heart, lung, kidneys, brain, and results in a 67% increase in mortality. The underlying cause of lupus is constitutive over-activation of the immune system driven by a class of potent immune signaling molecules called type I interferons.
Cyclic GAMP synthase (cGAS) is the trigger for autoimmunity: it senses DNA released from damaged cells. It produces signaling molecules that activate the pathway for the production of interferons, which circulate throughout the body, activating the immune system to attack critical organs and tissues. Multiple lines of evidence, including genetic knockouts of cGAS in mouse models of monogenic lupus, have clearly established that blocking cGAS is a compelling therapeutic strategy for lupus and other interferon-driven autoimmune diseases.
BellBrook is using structure-based design to develop two cGAS inhibitors with distinct mechanisms and organ distribution profiles. They plan to advance one of the molecules as a therapy for lupus and the other for treatment of Aicardi Goutieres syndrome, a rare childhood encephalopathy. The molecule being developed for lupus will be tested for in vivo efficacy in an innovative model of lupus-induced UV skin sensitivity developed by their collaborator, Dr. Keith Elkon.
The cGAS inhibitor program was enabled by the development of a proprietary biochemical HTS assay funded by a Phase I NIH SBIR grant awarded in April 2017 (grant number R43 GM123833-01), using the same approach that underlies BellBrook’s successful Transcreener HTS Assays. Consistent with their mission, the company recently commercialized the Transcreener cGAMP cGAS Assay to accelerate the discovery of cGAS inhibitors by other groups. The cGAS antagonists will be commercialized by BellBrook’s therapeutics subsidiary, Nudge Therapeutics, Inc.