SC Connecticut News

An enzyme-based treatment developed by Yale researchers mitigated autoimmunity and reduced death rates in both genetic and non-genetic mouse lupus models, a new study reveals. The findings, published June 17 in the journal JCI Insight, represent a significant advancement in autoimmune disease therapeutics.

Lupus is a chronic autoimmune disease that can cause inflammation and pain in any part of the body. "Although lupus was recently recognized as among the leading causes of death in young females in the U.S., we don’t really understand what causes the disease, which affects up to 1.5 million Americans," said Dr. Demetrios Braddock, associate professor of pathology at Yale School of Medicine and lead author of the study. "We were interested in an ultra-rare form of lupus reported in only 40 patients worldwide who lacked 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."

Weekly doses of the long-acting enzyme — engineered to replicate the activity of DNAse1L3 — prevented autoimmunity from developing in a mouse model of genetic lupus for a year, essentially halting lupus development. When dosing started after the initiation of the disease, the enzyme reduced death rates.

Initially conceived for a rare pediatric population, this therapeutic may also be effective for many more patients with lupus. This includes an estimated 35,000 patients with a pathogenic variant of DNAse1L3 that reduces the enzyme’s activity by about 80%. It also includes patients with lupus who have autoantibodies that neutralize DNAse1L3.

"We recently became aware that about one-third of patients with lupus have autoantibodies that block the function of DNAse1L3, mirroring patients who were born without the enzyme," said Dr. Felipe Andrade at Johns Hopkins University and co-author of the study. "Patients with antibodies to DNAse1L3 exhibited a more severe form of lupus with significant damage to organ systems such as kidneys."

To determine whether this new enzyme therapeutic could benefit these patients, Braddock's lab sent Andrade's team its human version for testing. Andrade’s lab found no evidence that neutralizing autoantibodies present in patients recognized this enzyme.

"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 stated.