Scientists Reveal the Harmful Impacts of Immune Hyperactivity in Down Syndrome and How to Normalize it by Repurposing Existing Drugs

In a new study, scientists at the University of Colorado Anschutz Medical Campus report the largest and deepest characterization of immune dysregulation in Down syndrome to date

AURORA, CO (July 23, 2023) – People with Down syndrome, the condition caused by an extra copy of chromosome 21, or trisomy 21, display chronic dysregulation of their immune system, which can contribute to high rates of autoimmune conditions and severe complications from respiratory infections.

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.

“We observed that interferon hyperactivity really shapes the biology of Down syndrome across the lifespan. Those with the highest interferon activity display increased signs of autoinflammation, stronger dysregulation of important growth factors, profound metabolic changes, and a vastly different immune system,” says Dr. Matthew Galbraith, leader of the Data Sciences Program at the Crnic Institute and one of the co-leading authors of the paper.

“These results clearly demonstrate that persons with Down syndrome with the highest levels of interferon activity show drastic changes in the immune system, such as increases in a type of T cells often involved in the development of autoimmune conditions, or depletion of B cells, which are important for response to vaccines” explains Keith Smith, co-leading author of the paper.

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.

“We observed a remarkable normalization of interferon hyperactivity when the participant was taking the JAK inhibitor. Consistently, her interferon metrics and other biomarkers of inflammation dropped from the abnormally high levels seen in Down syndrome down to the range observed in the general population, but not any lower. This indicates that the JAK inhibitor provided therapeutic benefit in terms of hair regrowth without suppressing the immune system below the normal range,” explains Dr. Angela Rachubinski, leader of the Clinical and Translational Sciences Program at the Crnic Institute and co-lead author of the study.

According to Dr. Joaquin Espinosa, executive director of the Crnic Institute and senior author of the paper, this study provided the rationale for two additional clinical trials for JAK inhibition in Down syndrome led by the Crnic Institute. “One study is focused on autoimmune skin conditions and another one is focused on Down Syndrome Regression Disorder, a rare but devastating condition characterized by sudden loss of  daily living skills and cognitive abilities.”

“This study is an example of the transformative scientific research taking place today that is enabled by increased funding from the National Institutes of Health through the INCLUDE Project, which in turn is the fruit of many years of advocacy and strong support from members of Congress. Naturally, none of these discoveries would be possible without the enthusiastic participation of our self-advocates and their families in research projects like the Human Trisome Project,” says Michelle Sie Whitten, president and CEO of the Global Down Syndrome Foundation, which supported the project with funding and outreach.

 

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About the University of Colorado Anschutz Medical Campus

The University of Colorado Anschutz Medical Campus is a world-class medical destination at the forefront of transformative science, medicine, education and patient care. The campus encompasses the University of Colorado health professional schools, more than 60 centers and institutes and two nationally ranked independent hospitals – UCHealth University of Colorado Hospital and Children’s Hospital Colorado – that treat more than two million adult and pediatric patients each year. Innovative, interconnected and highly collaborative, the University of Colorado Anschutz Medical Campus delivers life-changing treatments, patient care and professional training and conducts world-renowned research fueled by over $690 million in research grants. For more information, visit www.cuanschutz.edu.

About the Linda Crnic Institute for Down Syndrome

The Linda Crnic Institute for Down Syndrome is one of the only academic research centers fully devoted to improving the lives of people with Down syndrome through advanced biomedical research, spanning from basic science to translational and clinical investigations. Founded through the generous support and partnership of the Global Down Syndrome Foundation, the Anna and John J. Sie Foundation, and the University of Colorado, the Crnic Institute supports a thriving Down syndrome research program involving over 50 research teams across four campuses on the Colorado Front Range. To learn more, visit www.crnicinstitute.org or follow us on Facebook and Twitter @CrnicInstitute.

About Global Down Syndrome Foundation

The Global Down Syndrome Foundation (GLOBAL) is the largest non-profit in the U.S. working to save lives and dramatically improve health outcomes for people with Down syndrome. GLOBAL has donated more than $32 million to establish the first Down syndrome research institute supporting over 400 scientists and over 2,200 patients with Down syndrome from 33 states and 10 countries. Working closely with Congress and the National Institutes of Health, GLOBAL is the lead advocacy organization in the U.S. for Down syndrome research and care. GLOBAL has a membership of over 120 Down syndrome organizations worldwide, and is part of a network of Affiliates – the Crnic Institute for Down Syndrome, the Sie Center for Down Syndrome, and the University of Colorado Alzheimer’s and Cognition Center – all on the Anschutz Medical Campus.

GLOBAL’s widely circulated medical publications include Global Medical Care Guidelines for Adults with Down Syndrome, Prenatal Testing and Information about Down Syndrome, and the award-winning magazine Down Syndrome World TM . GLOBAL also organizes the Be Beautiful Be Yourself Fashion Show, the largest Down syndrome fundraiser in the world.

Visit globaldownsyndrome.org and follow us on social media (Facebook & Twitter: @GDSFoundation, Instagram: @globaldownsyndrome).

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