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NIH Scientists Find Gene Linked to Fatal Inflammatory Disease in Children

Repurposed drugs may offer first potential therapy

Researchers at the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), part of the National Institutes of Health, have identified a gene that underlies a very rare but devastating autoinflammatory condition in children. Several existing drugs have shown a therapeutic potential in laboratory studies, and one is currently being studied in children with the disease, which the researchers named STING-associated vasculopathy with onset in infancy (SAVI).

The new findings were published online July 17 in the New England Journal of Medicine.

In 2004, senior author Raphaela Goldbach-Mansky, MD, was called to advise on a patient with a baffling problem — a 10-year-old girl with signs of systemic inflammation, especially in the blood vessels, who had not responded to any of the medications her doctors had used to treat her.

She had blistering rashes on her fingers, toes, ears, nose, and cheeks, and had lost parts of her fingers to the disease. The child also had severe scarring in her lungs and was having trouble breathing. She had shown signs of the disease as an infant and had progressively worsened. She died a few years later.

By 2010, Goldbach-Mansky had seen two other patients with the same symptoms. She suspected that all three had the same disease, and that it was caused by a genetic defect that arose in the children themselves, rather than having been inherited from their parents, who were not affected. Her hunch suggested a strategy for identifying the genetic defect. By comparing the DNA of an affected child with the DNA of the child’s parents, scientists would be able to spot the differences and possibly identify the disease-causing mutation.

The DNA comparison revealed a novel mutation in a gene that encodes a protein called STING, a known signaling molecule whose activation leads to the production of interferon, a key immune regulator. When overproduced, however, interferon can trigger inflammation.

When the researchers tested the DNA of five other patients with similar symptoms, they found mutations in the same gene, confirming STING’s role in the disease. The excessive inflammation observed in patients, along with other evidence of interferon pathway activation, indicated that the mutations in STING boosted the protein’s activity.

Goldbach-Mansky’s team next looked for ways to reduce the inflammatory response in children with SAVI.

Several drugs —tofacitinib (Xeljanz, Pfizer), ruxolitinib (Jakafi, Incyte Corp.), and baricitinib (Eli Lilly/Incyte Corp., in clinical development) —are known to work by blocking the interferon pathway, so the researchers reasoned that these medications might be effective in people with SAVI as well. When they tested the effect of the drugs on SAVI patients’ blood cells in the lab, they saw a marked reduction in interferon-pathway activation.

In future work, Goldbach-Mansky’s team will investigate STING’s role in the interferon pathway and will examine how the mutations that cause SAVI lead to interferon overproduction.

“These mutations help us to understand the disease, but they also give us the rare opportunity to study the biology of the STING-mediated immune response,” said co-lead author Yin Liu, MD, PhD. “We don’t really understand how STING is activated or how the signal gets passed on to downstream molecules, but this work will help advance our understanding of this critically important pathway and its impact on other diseases.”

Source: NIH; July 17, 2014.

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