October 28, 2021
Two-day meeting focuses on sharing latest news and generating new scientific ideas
The Lupus Research Alliance (LRA) held our annual scientific conference, the Forum for Discovery, online for a second year given the continued concerns during the COVID-19 pandemic. The virtual capability allowed more than 150 funded investigators, scientific advisors, and partners from the pharmaceutical and biotech industries worldwide to participate in the meeting, sharing innovative insights and sparking innovative ideas to pursue further.
LRA President & CEO Kenneth Farber highlighted the success of several new treatment options for people living with rheumatic disease, specifically lupus despite the ongoing challenges of the coronavirus pandemic. These new treatment options, he said, “had their genesis in academic research by ambitious scientists, many funded by the LRA, working at hospitals, universities and medical schools around the world.”
The scientific program kicked off with an exciting keynote address from Dan Kastner, MD, PhD, Scientific Director of the Intramural Research Program at the National Human Genome Research Institute, part of the National Institutes of Health (NIH). Dr. Kastner discussed autoinflammatory diseases as a group of disorders that develop when the immune system attacks body’s own organs and tissues—and how his recent findings could apply more broadly to lupus.
Dr. Kastner and his team implemented a “gene-first” strategy to define new illnesses based on a permanent change in the DNA sequence — the blueprint for building our body’s cells — that makes up a gene shared among patients who display distinct clinical features. This approach, Dr. Kastner said, “may give rise to a new group of rheumatic diseases based on their molecular composition.” After analyzing a set of genes involved in the cell’s ability to dispose unneeded proteins in more than 2,500 patients who had come to the NIH with undiagnosed conditions, Dr. Kastner and his team discovered three middle-aged men who suffered from problems such as lung inflammation, skin lesions, and irritated cartilage in the nose and ears. They found that all three men had mutations in the UBA1 gene. Then they uncovered another 22 patients with the same mutation. Dr. Kastner and colleagues went on to name the condition as VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome in a 2020 publication. Harnessing genotype-first strategies, Dr. Kastner said, are likely to define new disorders that transcend current clinical boundaries.
After Dr. Kastner’s keynote address, 14 speakers shared their most recent discoveries from projects funded by the LRA. Presentations covered cutaneous lupus, mechanisms that may cause lupus, and the emerging therapies to treat this disease. Following highlights three presentations exemplifying the wide range of work covered.
Not Just Skin Deep: Insights into Cutaneous Lupus
Jillian Richmond, PhD, Assistant Professor of Dermatology at the University of Massachusetts Medical School, spoke about her work determining what attracts harmful immune cells into the skin of people living with a form of lupus that primarily affects the skin, known as cutaneous lupus, and whether existing drugs can keep the cells out to prevent damage. By using skin biopsies from people living with cutaneous lupus, Dr. Richmond is identifying the specific cells that produce molecules known as chemokines that can cause immune cells to invade the skin. Also using an animal model of the disease, Dr. Richmond is testing which class of drugs and what agents could block chemokines and/or make these molecules less inflammatory.
Expect the Unexpected: How One High-Risk Gene Variant Contributes to Lupus
Betsy Jo Barnes, PhD, Professor at Northwell Health Feinstein Institutes for Medical Research in New York, studies the interferon regulatory factor 5 (IRF5) gene. She and others have documented the IRF5 gene as a key player in the immune system and linked the gene to a higher risk for lupus. Her initial studies suggest that an IRF5 inhibitor could be a good candidate to treat lupus.
The IRF5 gene encodes the IRF5 protein that binds to specific regions of DNA and helps control the activity of certain genes. In lab and animal studies, Dr. Barnes developed a nontoxic inhibitor molecule that penetrates the cell membrane and enters into a variety of immune cells, including those called plasmacytoid dendritic cells, a rare type of immune cell known to secrete large quantities of type 1 interferons, which are the main disease drivers in lupus. Once the inhibitor enters cells, it keeps the IRF5 protein from traveling to the cell’s nucleus, which houses DNA and activating genes that may encode proteins involved in an autoimmune attack.
Dr. Barnes’ research also suggests that over-active IRF5 genes could serve as a clinically relevant indicator of the onset of lupus and separate patients in future clinical trials testing IRF5 inhibitors as potential treatments.
What’s Next for Lupus Therapies
Joshua Ooi, PhD, Senior Lecturer at Monash University School of Clinical Sciences in Melbourne, Australia, closed out the conference. Dr. Ooi spoke about a specialized group of T cells, called regulatory T cells (Tregs), and how he engineered these immune cells to block a person’s immune system from attacking itself.
Using blood from lupus patients, Dr. Ooi manufactured regulatory T cells that recognize a portion of the cell nucleus referred to as the Smith antigen. Smith antigens are proteins that are resistant to enzymes that degrade RNA—a molecule similar to DNA. When these engineered T cells recognize the Smith antigen, they can shut down harmful immune cells that wreak havoc on people living with lupus. Dr. Ooi plans to test In clinical trials whether and how these engineered cells suppress inflammatory responses and disease in patients with lupus.
With these and other presentations, the 2021 Forum for Discovery highlighted tremendous strides made over the past year toward better understanding of lupus and finding new targets for diagnosis and treatment.
“Facilitating an open and dynamic scientific exchange among LRA-funded investigators brings us closer to potential breakthroughs, better treatments and finding ways to prevent and cure lupus,” said Teodora Staeva, PhD, Chief Scientific Officer at the LRA, in her closing remarks.