Multidimensional definition of the interferonopathy of Down syndrome and its response to JAK inhibition
In a new study published in Science Advances, scientists at the Linda Crnic Institute for Down syndrome at the University of Colorado Anschutz Medical Campus report the largest and deepest characterization of immune dysregulation in Down syndrome to date. The findings also reveal important connections between immune hyperactivity and other aspects of Down syndrome and provide proof-of-principle evidence for a therapeutic strategy to restore immune balance in this population.
The Crnic Institute's previous research demonstrated that this immune dysregulation is associated with hyperactivity in the interferon response, the main defense against viruses. In addition, they showed interferon hyperactivity contributes to many hallmarks of Down syndrome in a mouse model, including congenital heart defects, developmental delays, cognitive impairments and malformation of the bone structures in the skull.
The most recent study reports the analysis of hundreds of blood samples from research participants enrolled in the Crnic Institute Human Trisome Project, a large cohort study of people with Down syndrome. Using a combination of large-scale data technologies, referred to as multi-omics, they defined associations between the degree of interferon hyperactivity and multiple physiological, metabolic, and immune processes dysregulated by the extra chromosome.
Previous studies have indicated that interferon hyperactivity could be ameliorated with a class of drugs known as "JAK inhibitors," which are approved for the treatment of a wide range of autoinflammatory conditions in the general population. However, the effects of JAK inhibitors on the biological processes modulated by trisomy 21 have not been extensively studied.
To advance this area of research, the Crnic Institute team monitored the effects of JAK inhibition on a research participant with Down syndrome taking the JAK inhibitor known as tofacitinib, or Xeljanz™, for the treatment of alopecia areata. Alopecia areata is an autoimmune form of hair loss more common in people with Down syndrome. Over the course of several years and under the care of their dermatologist, the participant provided blood samples while on the medicine and during voluntary interruptions of the treatment.