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“Lifting the hood” on rare immune diseases can help patients get the treatment they need

ford-1242192_1920Imagine you're driving and hear a worrisome noise coming from your vehicle. You pull over to the side of the road and add some oil. At first the noise quiets a little, but soon it's back, louder. You try adding antifreeze. That doesn't help. Next you change the wiper blades. Then you rotate the tires. The noise is still there.

This stressful scenario is, unfortunately, a pretty good analogy for the way that many inherited immune disorders are treated. When a patient has an unusual immune dysfunction, a few generalized therapies -- steroid medications, for instance -- are given to try to quiet the problem. But, until now, doctors have rarely had the ability to "lift the hood," figure out which specific part of the cellular machinery is malfunctioning, and treat that exact problem.

"One clinical picture can have so many different underlying causes," said pediatric hematologist Katja Weinacht, MD, PhD. When a patient's immune system is attacking the body's own red blood cells, for instance, non-specific treatments like steroids may not be enough to put immune disease into remission, Weinacht explained. And the treatments' side effects can exact a heavy price, especially from young patients.

Fortunately, as described in new research appearing today in the Journal of Allergy and Clinical Immunology, that picture is beginning to change. The paper, written by Weinacht and colleagues at Harvard University and Boston Children's Hospital, where she worked prior to coming to Stanford, describes how the team successfully identified and targeted the underlying disease mechanism in a 10-year-old girl suffering from a blood disease called Evans syndrome that had been triggered by a rare immune disorder. Today, Weinacht and colleagues from the stem cell transplant and immunology divisions at Lucile Packard Children's Hospital Stanford are working to establish a clinic for kids with inherited immune diseases, which fits nicely into the larger Stanford initiative to promote precision health.

As described in the new paper, the girl's body was destroying its own blood at such a furious pace that, for a while, she required almost-daily transfusions of red blood cells and platelets. She was also experiencing chronic fungal infections, diarrhea and lung disease. A bone marrow transplant could potentially have cured her, but her only sibling -- usually the best potential bone marrow donor -- wasn't an immune match. To make matters worse, the steroids that were helping to slow her anemia were also inducing diabetes.

So Weinacht's team identified the genetic defect underlying the child's disease, a gain-of-function mutation in the STAT1 gene. Since the girl's symptoms were so broad, the scientists used a series of lab assays to pinpoint exactly what parts of her cellular machinery were going awry. The mutation's effects rippled through the immune system in several directions, changing the levels and actions of a variety of immune cells and molecules and -- the researchers suspected -- accounting for the patient's unusual combination of symptoms.

Then they got lucky: They were able to identify an existing drug, ruxolitinib, that was already known to alter the parts of the cellular machinery affected by this child's gene mutation. The patient started getting the medication, and her doctors were able to wean her off of the non-specific treatments that had been causing damaging side effects. It worked. She has been in remission for more than a year, the paper reports. The scientists also document in detail the molecular and cellular changes caused by the drug that underlie the girl's improved health.

"With this drug we can reverse the phenotype of her disease, really getting to the root cause of the mechanism," Weinacht said. She's eager to bring the same approach to the aid of many more patients in the future.

Previously: A test for an autoimmune disease reveals what your cells are cooking up, Automating genetic analysis could speed diagnosis of rare disease and Stanford researchers work to translate genetic discoveries into widespread personalized medicine
Photo by Joshua_Willson

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