Infants born with Down syndrome, the genetic condition attributable to an additional copy of chromosome 21, or trisomy 21, are highly predisposed to congenital heart defects. It’s estimated that almost half of newborns with Down syndrome have a congenital heart malformation, and Down syndrome is recognized as probably the most common reason for congenital heart abnormalities. Despite many research efforts over several many years, the mechanisms by which trisomy 21 prevents proper formation of the center during embryonic development have remained unknown.

A recent study by scientists on the University of Colorado Anschutz Medical Campus reports the invention of a molecular mechanism contributing to defective heart development in Down syndrome. The research team, led by Dr. Kunhua Song, associate professor of drugs, employed a mixture of experiments using human cells with and without trisomy 21 and a mouse model of Down syndrome to light up the molecular basis of impaired heart formation.

Using pluripotent stem cells obtained from research participants within the Human Trisome Project, a big study of individuals with Down syndrome led by the Linda Crnic Institute for Down syndrome on the University of Colorado, the team modeled the initial steps of heart formation, or cardiogenesis, within the laboratory. They observed that trisomy 21 impaired cardiogenesis, and this malfunction was related to hyperactivity within the cellular response to viral infections, referred to as the interferon response. Then, using genetic and pharmacological approaches, they demonstrated that blocking the interferon response improved cardiogenesis within the laboratory.

We were surprised to see strong activity of the interferon response during differentiation of pluripotent stem cells into heart muscle cells with trisomy 21. We now appreciate that an abnormally high interferon response may very well be detrimental to early heart development.”

Dr. Kunhua Song, associate professor of drugs

The researchers continued their investigation into how exactly interferon hyperactivity impaired cardiogenesis, which led them to find that the interferon response inhibits a series of key molecular events required for heart development, reminiscent of the Wnt signaling pathway.

In accordance with Dr. Congwu Li, lead creator of the paper, “An excessive amount of interferon activity results in too little Wnt signaling, which in turn impairs heart muscle cell function. Discovering this cascade of events illuminates potential strategies to ameliorate improper heart formation in Down syndrome by toning down interferon signaling and/or bumping up Wnt signaling.”

To check this therapeutic strategy in a mouse model of Down syndrome, the investigators treated pregnant female mice with a medication that reduces the interferon response, referred to as a JAK inhibitor, and monitored the results on heart development within the embryos carrying a genetic alteration corresponding to trisomy 21. Indeed, treatment of pregnant mice with the JAK inhibitor caused a remarkable improvement in cardiogenesis in mice.

“These are very vital results, because they suggest a possible pharmacological strategy for pre-natal treatment of some of the harmful impacts of trisomy 21. Babies born with Down syndrome and congenital heart defects face numerous challenges, from the necessity of heart surgery soon after birth to long lasting impacts on their physiology later in life. Nonetheless, loads of additional research will probably be needed to define the security and efficacy of using JAK inhibitors while pregnant,” explains Dr. Joaquin Espinosa, executive director of the Linda Crnic Institute for Down syndrome and co-author of the paper.

Dr. Espinosa and his team are currently leading clinical trials studying the advantages of JAK inhibitors in older children and adults with Down syndrome.

These findings expand on a growing body of evidence demonstrating the harmful effects of interferon hyperactivity in Down syndrome, even during early stages of embryonic development. The outcomes also support the concept that most of the hallmarks of Down syndrome are driven by lifelong dysregulation of the immune system and that restoring immune balance could provide therapeutic advantages.

“This body of labor is proof of the rapid scientific advances that may happen with the proper investment of resources and the willingness of people with Down syndrome to take part in research,” says Dr. Espinosa. “We’re experiencing a real renaissance in the sector of Down syndrome research, fueled by strong support from the National Institutes of Health INCLUDE Project, which is the culmination of a few years of advocacy by the Global Down Syndrome Foundation. Due to these efforts, we’re confident that individuals with Down syndrome will live longer, healthier lives.”

Source:

University of Colorado Anschutz Medical Campus

Journal reference:

Chi, C., et al. (2023) Interferon hyperactivity impairs cardiogenesis in Down syndrome via downregulation of canonical Wnt signaling. iScience. doi.org/10.1016/j.isci.2023.107012.