A new international study led by researchers at B.C. Children’s Hospital has identified a gene variant that is responsible for a rare, debilitating allergic disease that has long confounded doctors and caused severe symptoms in patients.
The study, published Wednesday in the Journal of Experimental Medicine, found that a mutation in the STAT6 gene that made it go haywire was responsible for the severe allergic disease, which caused severe eczema, food allergies, asthma, severe episodes of anaphylaxis, and gastrointestinal disease in patients starting in their first year of life.
The STAT6 gene is a “master regulator of allergies,” said Dr. Stuart Turvey, a paediatric immunologist at Vancouver’s B.C. Children’s Hospital Research Institute. In these patients, researchers discovered a gain-of-function variant in their STAT6 gene, meaning it’s switched on all the time.
“Think of it like a thermostat or an accelerator on a car,” said Turvey. “We all have STAT6 and it’s usually at the right level. For these patients, the thermostat is turned right up or the accelerator is always turned on, so their bodies are always making these allergic responses.”
Turvey’s research started more than a decade ago when he was approached by a colleague who had treated a child with severe allergies, widespread eczema, food allergies, and impaired growth.
Turvey reached out to the patient, now a young adult, and asked him to participate in the research.
The research led Turvey and his colleagues to suspect the patient’s disease was due to a variant in the STAT6 gene. But to confirm their hypothesis, they needed more than one patient. Turvey and his team reached out to the global immunology community asking if they have patients with similar symptoms. Soon, they found another patient in Ontario. In six weeks, they uncovered 16 patients, ranging in age from three to 60, from 10 families across three continents, including in Hong Kong, France, the U.K., Italy, Iran, and Vietnam.
Genetic testing confirmed the patients had a type of gain-of-function variant in their STAT6 gene. Through the research, Turvey and his team were able to identify a treatment.
Dupilomab, approved by the U.S. FDA in 2017 and sold under the brand Dupixent, is already approved for use in Canada for severe eczema. It requires an application process and is not available over-the-counter.
Patients who have access to the drug have shown dramatic improvement, said Turvey.
One patient in Hong Kong suffered from very thick and painful skin from severe eczema growing up. He also had hair loss, infections in the bone marrow, and required multiple surgeries in his youth. In the two years since he’s been on the drug, he grew nearly eight inches at around age 20, as his body, with its overactive allergic reaction calmed down, was able to process nutrients properly.
Another patient, Widad Qubrossi, from Ontario also had severe allergies since birth. Within a couple weeks of birth, she threw up continuously, allergic to her mother’s breast milk.
All her life, doctors have told her they don’t know what’s causing her medical issues, which includes asthma, idiopathic eczema, respiratory issues. She lived an isolated life to help minimize her reactions, but also learned to strategically adapt to the limitations set by her disease and lead a fulfilling life.
Qubrossi has long hypothesized her condition was due to genes, and a few years ago, managed to see a geneticist who connected her with Turvey.
She has been taking Dupilomab for two years, and it has been a “game changer,” she said. “It’s been huge. What I have isn’t curable, but [the medication] has changed my quality of life drastically.” At age 36, “I’m able to work now.”
The breakthrough findings may have come too late for two patients in the study, including the Vancouver patient whose participation kickstarted the study. They both died from the disease: One from anaphylaxis at age 20, the other from a cerebral aneurysm at age 35.
With the evidence, however, patients with gain-of-function STAT6 variants now have an effective, targeted therapy. “We can now make a strong recommendation that this is a very effective medicine for this new disease,” said Turvey.
He said specialists with patients exhibiting these symptoms should consider genetic testing. Most cases of severe allergic disease are of unknown causes, but there are variants in about 30 genes that are known to cause severe allergies.
Identifying the gene variant that leads to severe allergic diseases can help with the diagnoses and treatments and potentially uncover new ways of preventing and treating allergies, both severe and common, he added. “By understanding the rare, severe diseases, we start to understand the biology of common allergies that affect 10 to 15 per cent of people.”
