Media advisory
Thursday, May 30, 2024
NIH researchers find new pathways to treatment for autoimmune polyendocrine syndrome type 1.
What
A drug approved to treat several autoimmune diseases and cancers successfully alleviated the symptoms of a rare genetic syndrome called autoimmune polyendocrine syndrome type 1 (APS-1). The researchers identified the treatment based on their discovery that the syndrome is associated with elevated levels of interferon-gamma (IFN-gamma), a protein involved in immune system responses, providing new insights into the role of IFN-gamma in autoimmunity. . The study, led by researchers at the National Institute of Allergy and Infectious Diseases of the National Institutes of Health, was published today in New England Journal of Medicine.
In a three-phase study conducted in mice and humans, researchers examined how APS-1 causes autoimmune disease. The syndrome is characterized by multiple organ dysfunction, usually beginning in childhood, and is fatal in more than 30% of cases. This inherited syndrome is caused by a deficiency in a gene that prevents T cells of the immune system from attacking the body’s cells, leading to autoimmunity; chronic yeast infections on the skin, nails and mucous membranes; and insufficient hormone production by endocrine organs, such as the adrenal glands. Symptoms include stomach irritation, liver inflammation, lung irritation, hair loss, loss of skin pigmentation, tissue damage and organ failure.
In the first phase 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 tissue 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 target route for treatment.
In the second phase of the study, the scientists examined mice with the same gene deficiency that causes APS-1 in humans, finding that the animals also experienced autoimmune tissue damage and elevated levels of IFN-gamma. Mice also lacking the gene for IFN-gamma did not have autoimmune tissue damage, indicating a direct link between IFN-gamma and APS-1 symptoms. With this understanding, the researchers searched for a drug that could be used to decrease the activity of IFN-gamma in humans. They chose ruxolitinib, a Janus kinase inhibitor, because it works by shutting down the IFN-gamma-driven pathway. When ruxolitinib was administered to mice deficient in the gene 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 can alleviate the effects of the gene deficiency, suggesting that it may be effective for treating APS-1 in humans.
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 phase of the study. Dosing and regimens were tailored to individuals and treatments continued for more than a year. The drug was safe and well tolerated, and symptom improvement was seen in all study participants. Blood and tissue analyzes revealed decreased production of IFN-gamma by T cells, as well as normalized levels of IFN-gamma in the blood. Many symptoms associated with APS-1 were reduced, including hair loss, oral yeast infections, stomach and intestinal irritation, hives, and thyroid inflammation.
The results revealed that normalizing IFN-gamma levels using ruxolitinib can reduce the harmful effects of APS-1 in humans. The scientists note 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. They write that understanding the role of IFN-gamma in autoimmunity may lead to the development of treatments for related diseases. This study highlights the importance of finding causes and treatments for rare diseases.
Editorial note: APS-1 is also known as polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) in the literature.
Reference
V Oikonomou et al. The role of interferon-gamma in polyendocrine autoimmune syndrome type 1. New England Journal of Medicine DOI: 10.1056/NEJMoa2312665 (2024).
WHO
Michail S. Lionakis, MD, Sc.D., chief of NIAID’s Fungal Pathogenesis Section and deputy chief of NIAID’s Laboratory of Clinical Immunology and Microbiology, is available to discuss this research.
NIAID conducts and supports research—at NIH, across the United States, and around the world—to study the causes of infectious and immune-mediated diseases and to develop better tools for preventing, diagnosing, and treating these diseases. News releases, fact sheets, and other NIAID-related materials are available on the NIAID website.
About the National Institutes of Health (NIH):NIH, the national medical research agency, includes 27 institutes and centers and is a component of the US Department of Health and Human Services. NIH is the lead federal agency that conducts and supports basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.
NIH…Turning discovery into health®
#existing #drug #holds #promise #treatment #rare #genetic #disorder
Image Source : www.nih.gov