Down syndrome impairs infant heart development through cellular response: Study

Trisomy 21, also known as Down syndrome — can hamper heart formation in embryos and triggers hyperactive cellular response to viral attacks, say scientists. Trisomy 21 arises due to an additional chromosome.

Using stem cells obtained from research participants with Down syndrome and a mouse model of the syndrome, the scientists at the University of Colorado Anschutz Medical Campus, US, modelled cardiogenesis, or heart formation, in the lab.

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

Also Read: World Sickle Cell Day | Sickle cell anaemia 11 times deadlier than thought: Study

“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.

Also Read: World Blood Donor Day: Giving blood is good for your health; find out why

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.

Also Read: Engineered white blood cells can eliminate cancer, says study

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.

(With agency inputs)