Carola Vinuesa, MD, PhD: Gene Variant TLR7 Causes Lupus

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Carola Vinuesa, MD, PhD, recipient of the Lupus Research Alliance Lupus Insight Prize, discovered a mutation in a specific human gene that causes systemic lupus erythematosus.

HCPLive Rheumatology interviewed Carola Vinuesa, MD, PhD, Royal Society Wolfson fellow and assistant research director at the Francis Crick Institute, the 2023 recipient of the Lupus Research Alliance Lupus Insight Prize. She and her team discovered a mutation in a specific human gene that causes systemic lupus erythematosus (SLE), which may be an important target for the development of new treatment.

Vinuesa and her team have been dedicated to understanding the causes of lupus for many years, with previous genetic studies using spontaneous mouse models. While they found genes of interest, the mouse models didn't accurately represent the human variants, which limited their progress.

When new genetic technologies for whole genome sequencing became available, they decided to sequence the genomes of actual patients and specifically focused on severe cases of pediatric onset lupus, as they believed identifying a single gene responsible for the disease might be possible in certain cases.

The discovery of the TLR7 gain-of-function variant showed promise for identifying a specific cause of lupus.

“This variant is particularly intriguing as it affects a gene that acts as a receptor for viral RNA, responsible for viral nucleic acid recognition,” Vinuesa explained. “Moreover, the gene is located on the X chromosome, meaning women, who typically have 2 copies of the X chromosome, may be more affected if the gene is overactive.”

Additionally, the variant was not found in the parents, suggesting it arose either during embryonic development or in certain cells of the parents. Mutations like this often play a role in severe illnesses in children. While previous associations existed between autoimmunity and the gene itself, there had been no definitive proof that defects in TLR7 cause disease in humans.

Identifying the pathway is often more important than finding it in every patient within that pathway. For example, therapies targeting the TLR7 receptor or inhibiting its activity may be effective for a subset or significant fraction of lupus patients.

Future research will focus on gaining a deeper understanding of the disease itself. Specifically, they aim to determine how many patients' disease depends on TLR7 signaling, whether other pathways are involved, and if most pathways converge on this signaling. Notably, evidence suggests that a number of patients with lupus exhibit an activated TLR7 receptor. Vinuesa and her team hope to identify which patients would benefit most from therapies targeting this pathway, differentiating them from those with different types of lupus.

“Our team and numerous researchers worldwide are working diligently to unravel the complexities of lupus,” Vinuesa concluded. “Notably, there are already medications targeting the TLR7 pathway undergoing clinical trials. In the near future, we should have a better understanding of their effectiveness in treating the disease.”