A new study led by researchers at the National Institutes of Health’s (NIH) National Institute of Allergy and Infectious Diseases (NIAID) demonstrates a drug approved to treat certain autoimmune diseases and cancers successfully alleviated symptoms of a rare genetic syndrome called autoimmune polyendocrine syndrome type 1 (APS-1).

The findings are published in the New England Journal of Medicine in an article titled, “The Role of Interferon-γ in Autoimmune Polyendocrine Syndrome Type 1.”

“Autoimmune polyendocrine syndrome type 1 (APS-1) is a life-threatening, autosomal recessive syndrome caused by autoimmune regulator (AIRE) deficiency. In APS-1, self-reactive T cells escape thymic negative selection, infiltrate organs, and drive autoimmune injury. The effector mechanisms governing T-cell–mediated damage in APS-1 remain poorly understood.”

Researchers identified the treatment based on their discovery that the syndrome is linked to elevated levels of interferon-gamma (IFN-gamma).

In a three-stage study, conducted in mice and people, the researchers examined how APS-1 causes autoimmune disease. In the first stage of this study, researchers led by scientists in NIAID’s Laboratory of Clinical Immunology and Microbiology examined the natural history of APS-1 in 110 adults and children. Blood and tissues were analyzed to compare gene and protein expression in people with and without APS-1. They found elevated IFN-gamma responses in the blood and tissues of people with APS-1, indicating that IFN-gamma may play an important role in the disease and provide a pathway to target for treatment.

In the second stage of the study, the scientists examined mice with the same gene deficiency that causes APS-1 in people, finding that the animals also experienced autoimmune tissue damage and elevated IFN-gamma levels. Mice also deficient in the gene for IFN-gamma did not have autoimmune tissue damage, which showed a direct link between IFN-gamma and APS-1 symptoms. With this understanding, the researchers looked for a drug that could be used to lower IFN-gamma activity in people. They selected ruxolitinib, a Janus kinase inhibitor, because it acts by shutting down the pathway driven by IFN-gamma. When ruxolitinib was administered to the mice with the gene deficiency that causes APS-1, IFN-gamma responses were normalized and T cells were prevented from infiltrating tissues and damaging organs. These results showed that ruxolitinib could alleviate effects of the gene deficiency.

The researchers administered ruxolitinib, which was supplied by the NIH Clinical Center, to five people—two adults and three children—with APS-1 in the third stage of the study. The drug was safe and tolerated well, and improvement in symptoms was seen in all study participants. Blood and tissue analyses revealed decreased production of IFN-gamma from T cells, as well as normalized levels of IFN-gamma in the blood.

The results revealed that normalizing IFN-gamma levels using ruxolitinib could reduce the damaging effects of APS-1 in people. The scientists noted that a study with a larger and more diverse group of patients is needed to determine whether ruxolitinib and similar drugs are suitable treatments for individuals with APS-1.

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