The Judith and Stewart Colton Center for Autoimmunity at NYU Langone Health continues to expand its pilot grant program. It has supported nearly 20 interdisciplinary collaborations to date, with several advancing through the translational pipeline toward potential clinical applications in diagnosing, treating, and preventing autoimmune diseases.

The slate of promising studies will soon be joined by seven additional pilot projects approved for funding for 2019, notes Colton Center director Timothy Niewold, MD, professor of medicine and pathology.

Gaining Insight into Myasthenia Gravis and Rheumatoid Arthritis

Among the newly funded pilot projects is an investigation of the properties of autoantibodies linked to the rare autoimmune disorder myasthenia gravis. Led by researchers from the Skirball Institute of Biomolecular Medicine—Steven J. Burden, PhD, professor of neuroscience and physiology and cell biology; Damian C. Ekiert, PhD, assistant professor of cell biology and microbiology; and Gira Bhabha, PhD, assistant professor of cell biology—the team is seeking to understand why autoantibodies bind a protein called muscle-specific kinase, or MuSK, blocking normal nerve-to-muscle signaling and leading to pronounced muscle weakness in a subset of patients. If the researchers can reveal a target on the MuSK protein, Dr. Niewold says, they may be able to develop a “dummy” target that soaks up the autoantibodies and restores proper signaling and muscle function.

A second pilot focuses on blood-based biomarkers for rheumatoid arthritis to aid clinical decision-making on behalf of patients who fail to respond to the first-line therapy, methotrexate. For these patients, second-line alternatives are currently limited by a lack of evidence. The project, led by Theresa L. Wampler Muskardin, MD, assistant professor of medicine, has uncovered preliminary data that type 1 interferon levels in the blood might predict a patient’s response to tumor necrosis factor (TNF) inhibitor drugs.

Dr. Muskardin is now working to validate her hypothesis in a large clinical cohort. At the same time, she is staining synovial tissue in the joints of patients with rheumatoid arthritis to clarify the underlying biology of the type 1 interferon pathway and its ability to predict a TNF inhibitor nonresponse.

Mapping the Origins of Lupus

In collaboration with Jef D. Boeke, PhD, professor of biochemistry and molecular pharmacology and director of the Institute for Systems Genetics at NYU Langone, Dr. Niewold is leading a project to identify the most critical regions of interferon regulatory factor 5 (IRF5), a gene linked to systemic lupus erythematosus (SLE) risk. “When we look at the areas potentially causing the risk, there are at least four suspects, and they are always in the room,” Dr. Niewold says. “You can never question them separately. This new approach allows us to look at each element separately and understand how it is causing risk of disease.”

Using Dr. Boeke’s high-throughput method to create synthetic chromosomes, the team isolates and analyzes each implicated gene region on separate chromosomes—and in various combinations—to determine which region or synergy of regions may be driving the elevated risk. “This same approach could then be extended to other genes, and you could really start to map the origins of autoimmune disease,” says Dr. Boeke.

A New Push Through the Clinical Pipeline

In collaboration with NYU Langone’s Office of Therapeutics Alliances, two of the center’s previous pilot projects have taken major steps toward translating their scientific findings to clinical use.

One effort, led by Boris Reizis, PhD, professor of medicine and pathology, targets the enzyme DNASE1L3 as a potential therapeutic agent for lupus. Dr. Reizis’s group has developed a mouse model with DNASE1L3 deficiency, which exhibits features of SLE, particularly renal disease. The researchers are now working to develop methods to treat disease by targeting this pathway.

A second project, led by Gregg Silverman, MD, professor of medicine and pathology, is working toward a blood test based on a biomarker that could predict lupus nephritis. Dr. Silverman found that a gram-positive bacterial genus, Ruminococcus, identified in the gut microbiome of some patients with lupus, may contribute to kidney disease and that such patients carry blood-borne antibodies against the microbe.