Smiling infant

Credit: Petr Kratochvil

Investigators say they’ve discovered the genetic defect that underlies STING-associated vasculopathy with onset in infancy (SAVI), which has led to a potential treatment for this rare condition.

The team found that SAVI patients have a mutation in a gene that encodes the protein STING, a signaling molecule whose activation leads to interferon production.

So it followed that JAK inhibitors, which block the interferon pathway, showed activity in samples from SAVI patients.

And based on these results, the investigators are enrolling SAVI patients on a compassionate use protocol for the JAK1/2 inhibitor baricitinib.

Raphaela Goldbach-Mansky, MD, of the National Institute of Arthritis and Musculoskeletal and Skin Diseases in Bethesda, Maryland, and her colleagues described the results in NEJM.

The research began in 2004, when Dr Goldbach-Mansky was called upon to advise on a patient with a baffling problem. The 10-year-old girl had signs of systemic inflammation, especially in the blood vessels, and she had not responded to any treatments.

She had blistering rashes on her fingers, toes, ears, nose, and cheeks, and she 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, Dr Goldbach-Mansky had seen 2 other patients with the same symptoms. She suspected that all 3 had the same disease, and it was caused by a genetic defect that arose in the children, as their parents 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 TMEM173, the gene encoding STING, a protein whose activation leads to the production of interferon. When overproduced, interferon can trigger inflammation.

“Blood tests on the affected children had shown high levels of interferon-induced proteins, so we were not surprised when the mutated gene turned out to be related to interferon signaling,” Dr Goldbach-Mansky said.

When they tested the DNA of 5 other patients with similar symptoms, the investigators found mutations in the same gene, confirming STING’s role in the disease. The excessive inflammation observed in the patients, along with other evidence of interferon pathway activation, indicated that mutations in STING boosted the protein’s activity.

The investigators found that STING was present in high levels in the cells lining the blood vessels and the lungs, which would likely explain why these tissues are predominantly affected by SAVI.

Dr Goldbach-Mansky’s team next looked for ways to dampen the inflammatory response in patients with SAVI.

“When mutations that cause autoinflammatory conditions hit an important pathway, the outcome for patients can be dismal,” Dr Goldbach-Mansky said. “But because SAVI is caused by a single gene defect and interferon has such a strong role, I’m optimistic that we’ll be able to target the pathway and potentially make a huge difference in the lives of these children.”

The JAK inhibitors tofacitinib, ruxolitinib, and baricitinib are known to work by blocking the interferon pathway, so the investigators reasoned the drugs might be effective in patients with SAVI as well.

When they tested the effect of the drugs on SAVI patients’ blood cells in the lab, the team saw a marked reduction in interferon-pathway activation.

The investigators are now enrolling SAVI patients in a compassionate use protocol for baricitinib.

Dr Goldbach-Mansky’s team is also planning to investigate STING’s exact role in the interferon pathway and examine how the mutations that cause SAVI lead to interferon overproduction.

Group takes first step toward treating rare pediatric disease