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Engineered enzyme developed at Yale shows promise for patients with lupus

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Staff at TrialSite | Quality Journalism
Jun. 27, 2024, 6:00 p.m.

Yale researchers have created an enzyme-based treatment that diminished autoimmunity and reduced death rates in both genetic and non-genetic mouse lupus models, according to a new study published in the journal JCI Insight.

Lupus is a chronic autoimmune disease that can cause inflammation and pain in any part of the body. The disease affects up to 1.5 million people in the United States, but the exact cause is unknown.

The Yale research team focused on an ultra-rare form of lupus affecting only 40 patients worldwide who lack an enzyme called DNAse1L3. Because all children without the enzyme developed lupus, “we thought it could tell us about both disease mechanisms and new therapies," said Dr. Demetrios Braddock, associate professor of pathology at Yale School of Medicine and lead author of the study.

The long-acting enzyme was engineered to replicate the activity of DNAse1L3 and be absorbed and used by the body. When tested in a mouse model of genetic lupus, weekly doses prevented autoimmunity from developing for a year, essentially halting lupus development. When dosing started after the initiation of the disease, the enzyme reduced death rates.

Although the therapeutic was initially conceived for a rare pediatric population, it may also be effective in other patients with lupus, said the researchers. This could include patients with a pathogenic variant of DNAse1L3 that reduces the enzyme's activity by almost 80%, as well as patients with lupus who have autoantibodies that neutralize DNAse1L3.

To determine whether the new enzyme therapeutic could benefit these patients, the Yale team sent the human version of its enzyme for testing to the laboratory of Dr. Felipe Andrade at Johns Hopkins University in 2023. Andrade is co-author of the new study. Andrade's lab found no evidence that the enzyme was recognized by neutralizing autoantibodies present in patients with lupus.

"The lack of recognition by neutralizing autoantibodies in the lupus population to our potential therapy bodes well that our approach would also help these patients," Braddock said.

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