Existing drug promising for rare genetic disorder

A drug that has been previously approved for treating certain autoimmune diseases and cancers has shown promising results in alleviating symptoms of autoimmune polyendocrine syndrome type 1 (APS-1), a rare genetic disorder. This advancement is based on research that discovered a connection between APS-1 and elevated levels of interferon-gamma (IFN-gamma), a protein pivotal in immune responses. This finding provides valuable insights into the role of IFN-gamma in autoimmune conditions.

The study, conducted by researchers at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, was published in the New England Journal of Medicine. It comprised three stages involving both human and animal subjects to understand APS-1 and explore potential treatments.

APS-1 is characterized by the dysfunction of multiple organs, typically beginning in childhood, and has a mortality rate exceeding 30%. The syndrome arises due to a genetic defect that allows T cells of the immune system to attack the body's cells, leading to autoimmunity, chronic yeast infections, and inadequate hormone production from endocrine organs like the adrenal glands. Symptoms include stomach irritation, liver inflammation, lung issues, hair loss, loss of skin pigmentation, tissue damage, and organ failure.

In the initial phase, the researchers studied the natural history of APS-1 in 110 adults and children. They analyzed blood and tissue samples to compare gene and protein expression between those with and without APS-1. The team found that individuals with APS-1 had elevated IFN-gamma levels, suggesting that this protein plays a crucial role in the disease and could be a target for treatment.

During the second phase, the scientists examined mice with the same genetic defect causing APS-1 in humans. These mice also exhibited autoimmune tissue damage and high IFN-gamma levels. Notably, mice lacking the gene for IFN-gamma did not suffer from autoimmune tissue damage, establishing a direct link between IFN-gamma and APS-1 symptoms. With this understanding, researchers sought a drug to reduce IFN-gamma activity. They chose ruxolitinib, a Janus kinase inhibitor, which blocks the pathway activated by IFN-gamma. Administering ruxolitinib to the genetically deficient mice normalized IFN-gamma responses, preventing T cells from attacking tissues and organs. This indicated that ruxolitinib could potentially treat APS-1 in humans.

In the final phase, ruxolitinib was given to five APS-1 patients—two adults and three children—supplied by the NIH Clinical Center. The treatment regimen was personalized for each participant and continued for over a year. The drug was found to be safe and well-tolerated, with all participants showing symptom improvement. Blood and tissue analyses showed reduced IFN-gamma production from T cells and normalized blood IFN-gamma levels. Symptoms like hair loss, oral yeast infections, gastrointestinal irritation, hives, and thyroid inflammation were notably decreased.

These findings suggest that ruxolitinib can mitigate the harmful effects of APS-1 by normalizing IFN-gamma levels. However, the researchers emphasize the need for larger, more diverse studies to confirm ruxolitinib’s efficacy and safety for APS-1 patients. Furthermore, understanding IFN-gamma's role in autoimmunity could pave the way for developing treatments for other related diseases. This research underscores the significance of identifying causes and treatments for rare diseases, highlighting the potential for broader applications in autoimmune therapy.