Scientist wins $100K prize for identifying lupus-causing mutations

Carola Vinuesa's discovery 'paved the way for the development of novel lupus treatments'

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by Lindsey Shapiro |

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The Lupus Research Alliance has awarded its 2023 Lupus Insight Prize to a researcher for her pioneering discovery that mutations in the TLR7 gene are a cause of systemic lupus erythematosus (SLE).

Carola Vinuesa, MD, PhD, assistant research director at The Francis Crick Institute in London, was given the award, including a $100,000 grant, at the recent 23rd Federation of Clinical Immunology Societies 2023 meeting in Boston.

The Lupus Insight Prize is granted each year to an investigator who has made significant discoveries that advance the understanding of lupus mechanisms, diagnosis, or treatment.

“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,” Vinuesa said in a press release. “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.”

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Underlying cause of autoimmune attacks in lupus not fully understood

An autoimmune disease, lupus is marked by the immune system’s misdirected attack against its own tissues. Yet, the underlying cause of these attacks are not fully understood.

“The cause of lupus is unknown; however, it is known that genetics and environmental factors contribute to the diagnosis and progression of the disease,” Vinuesa said. “Childhood-onset of SLE is rare and often severe, suggesting a potential underlying genetic component.”

In a study published in the journal Nature last year, Vinuesa and her team examined the genetic profile of a 7-year-old girl in Spain with severe lupus. They identified a mutation in the TLR7 gene, which encodes a protein called toll-like receptor 7, or TLR7.

Subsequent analyses identified mutations in TLR7 in two additional SLE patients.

TLR7 is involved in the activation of the immune system upon detection of viral genetic material. Specifically, the protein recognizes viral RNA, an intermediate molecule that serves as a template for protein production.

To learn more about how the mutation might contribute to SLE, researchers genetically edited mice to house the same mutation. They found that mice exhibited signs of autoimmunity similar to those seen in the patient, including the presence of self-reactive antibodies, immune activation, and severe organ damage.

The mutation appeared to increase TLR7’s response to guanosine, the molecule it interacts with, ultimately causing the protein to be more active and have an increased sensitivity to RNA molecules it wouldn’t normally react to.

Ultimately, that made it more likely to react not only to viral RNA, but also to the body’s own RNA, thus prompting immune B-cells to launch misdirected immune attacks.

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TLR7 is on X chromosome which may explain why lupus affects more women

TLR7 resides on the X chromosome, of which girls have two copies and boys have one. Since neither copy of the gene is turned off in women, they have a higher “gene dose” of TLR7. Researchers believe that might in part explain why lupus is more prevalent in women.

While it had been previously found that lupus patients exhibit increased TLR7 activity, no disease-causing mutations in TLR7 had been identified up to that point.

“Although mutations in TLR7 may be rare, many patients with lupus show signs of hyperactivity of TLR7 signaling,” said Teodora Staeva, PhD, vice president and chief scientific officer of the Lupus Research Alliance. “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.”

Indeed, efforts are underway to develop treatments that target TLR7. For example, Bristol-Myers Squibbs’ afimetoran and EMD Serono’s enpatoran are both in Phase 2 testing for lupus. Both are selective blockers of TLR7 and TLR8, a related protein.