Lupus Research Alliance honors Carola Vinuesa, MD, PhD, for discovering a specific gene variant that causes lupus in some patients

(Press-News.org) NEW YORK, NY – June 22, 2023 – The Lupus Research Alliance awarded its 2023 Lupus Insight Prize to Carola Vinuesa, MD, PhD, of The Francis Crick Institute, for her seminal discovery that a mutation in a specific human gene causes systemic lupus erythematosus (SLE), uncovering an important target for the development of novel treatment. The Lupus Insight Prize is awarded each year to an outstanding investigator who has made a significant discovery that will advance our understanding of the pathogenesis, diagnosis, or treatment of lupus.

Dr. Vinuesa and her team analyzed the genome, or genetic makeup, of a seven-year-old girl with lupus and identified a mutation in the gene that encodes toll-like receptor 7 (TLR7). TLR7 activates the immune system upon detecting viral RNA. The mutation Dr. Vinuesa identified causes TLR7 to not only respond to viral RNA, but to the body’s own RNA, driving autoimmune diseases such as SLE. Many lupus patients display increased TLR7 activity; however, disease-causing mutations in the TLR7 gene had not been identified.

“Although mutations in TLR7 may be rare, many patients with lupus show signs of hyperactivity of TLR7 signaling. This groundbreaking finding provides critical insight into lupus disease mechanisms and has paved the way for the development of novel lupus treatments targeting dysfunctional TLR7,” said Teodora Staeva, PhD, Vice President and Chief Scientific Officer of the Lupus Research Alliance.

The Prize, which includes a $100,000 grant award, was formally presented during the Lupus Insight Prize session at the 23rd Federation of Clinical Immunology Societies (FOCIS) 2023 meeting in Boston. World-renowned Gary Koretzky, MD, PhD, Professor at Weill Cornell Medicine and Chair of the LRA Science Advisory Board, presented the award to Dr. Vinuesa.

“The cause of lupus is unknown; however, it is known that genetics and environmental factors contribute to the diagnosis and progression of the disease. Childhood-onset of SLE is rare and often severe, suggesting a potential underlying genetic component,” said Dr. Vinuesa. “I am honored to receive this most prestigious award from the Lupus Research Alliance in recognition of our discovery of a genetic cause of lupus. This grant will be used to further advance our research so that we can help inform the development of new targeted treatments for both kids and adults.”

Dr. Vinuesa is a Royal Society Wolfson fellow and Assistant Research Director at The Francis Crick Institute in London, England. Prior to joining The Francis Crick Institute, Dr. Vinuesa established and directed the National Health and Medical Research Council (NHMRC) Centre of Research Excellence in Personalized Immunology. The NHMRC is the main statutory authority of the Australian Government responsible for medical research. A Fellow of the Royal Society of London (FRS) and of the Australian Academy of Science (FAA), she is the recipient of many distinguished awards, including the Science Minister's Prize for Life Scientist of the Year, the Gottschalk Medal of the Australian Academy of Sciences, and the inaugural recipient of the CSL Young Florey Medal.

Novel genetic mutation reveals critical driver of lupus

Dr. Vinuesa and her research team sequenced the genome of a seven-year-old girl with severe lupus to identify novel disease-causing variants. Whole-genome sequencing revealed a mutation in the gene that encodes a protein called toll-like receptor 7 (TLR7). To determine whether the TLR7 mutation identified causes lupus, Dr. Vinuesa’s team used a gene-editing tool, CRISPR/Cas9, to introduce the specific variant into mice. Mice with the TLR7 mutation exhibited hallmark symptoms of autoimmunity, similar to those observed in the young girl, including the presence of self-reactive antibodies (autoantibodies) and end-stage organ damage. The mutation identified is a gain-of-function mutation, meaning it enhances the activity of TLR7. The researchers found that the mutation caused increased affinity of TLR7 for its binding partner, guanosine, resulting in elevated activity of TLR7 and its associated signaling pathways. The mutation also caused heightened sensitivity of TLR7 to single-stranded RNA that would not typically activate it, making it more likely to incorrectly identify a patient's own tissue as a foreign pathogen such as a virus or bacteria. Because TLR7 is in the X chromosome and is not silenced as other X-chromosome genes are, females have a higher gene dose of TLR7, and this is likely to explain or contribute to the increased prevalence of lupus in females.

This research was published last year in the journal Nature.

About Lupus

Lupus is a chronic, complex autoimmune disease that affects millions of people worldwide. More than 90% of people with lupus are women, often striking during the childbearing years of 15-45. African Americans, Latin Americans, Asians, and Native Americans are at two to three times greater risk than Caucasians. In lupus, the immune system, which is designed to protect against infection, creates antibodies that can attack any part of the body, including the kidneys, brain, heart, lungs, blood, skin, and joints. Symptoms vary from skin rash and debilitating fatigue to life-threatening organ failures.

About the Lupus Research Alliance

The Lupus Research Alliance aims to transform treatment while advancing toward a cure by funding the most innovative lupus research in the world. The organization's rigorous peer review grant process fosters diverse scientific talent who are driving discovery toward better diagnostics, improved treatments and, ultimately, a cure for lupus. As the Lupus Research Alliance's Board of Directors funds all administrative and fundraising costs, 100% of all donations are dedicated to supporting lupus research programs. For more information, please visit www.lupusresearch.org and on social media at:  Instagram; Twitter;  LinkedIn; and Facebook.

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