Impaired heart development in infants linked to Down syndrome chromosome: Study

A team of scientists at the University of Colorado Anschutz Medical Campus in the US have conducted research demonstrating how trisomy 21, the presence of an additional copy of chromosome 21 causing Down syndrome, affects the development of the heart during embryonic stages.

They discovered that this genetic condition hinders proper heart formation and leads to an overactive cellular response when the heart is exposed to viral attacks.

To investigate this further, the scientists used stem cells obtained from individuals with Down syndrome who participated in the study, along with a mouse model of the syndrome.

In their laboratory, they successfully recreated the process of cardiogenesis, shedding light on the underlying mechanisms of heart development in those with Down syndrome.

The scientists demonstrated that blocking the antiviral cellular response, or the interferon response, improved cardiogenesis.

"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 could be detrimental to early heart development," explained Kunhua Song, associate professor of medicine and lead researcher.

Further, they found, interferon hyperactivity impaired cardiogenesis by inhibiting a series of key molecular events required for heart development, such as the Wnt signalling pathway.

According to Congwu Li, lead author of the paper published in the journal iScience, "Too much interferon activity leads to too little Wnt signalling, 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 signalling and/or bumping up Wnt signalling."

Testing this therapeutic strategy in a mouse model of Down syndrome, the investigators treated pregnant female mice with JAK inhibitors, known to reduce interferon response. They then monitored the effects on heart development in the embryos carrying a genetic alteration equivalent to trisomy 21.

The researchers noticed a remarkable improvement in cardiogenesis in mice.

"These are very important results, because they suggest a potential pharmacological strategy for pre-natal treatment of one of the most harmful impacts of trisomy 21.

"Babies born with Down syndrome and congenital heart defects face a number of challenges, from the need of heart surgery soon after birth to long lasting impacts on their physiology later in life.

"However, a lot of additional research will be needed to define the safety and efficacy of using JAK inhibitors during pregnancy," said Joaquin Espinosa, executive director of the Linda Crnic Institute for Down syndrome at the University of Colorado and co-author of the paper.

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

These findings expand, they said, on a growing body of evidence demonstrating the harmful effects of interferon hyperactivity in Down syndrome, even during early stages of embryonic development.

The results also support the idea, they said, that many of the hallmarks of Down syndrome are driven by lifelong dysregulation of the immune system and that restoring immune balance could provide therapeutic benefits.

(PTI)