CU Uncovers a "Game-Changing Discovery" in Down Syndrome

In 1959, a French geneticist discovered that people with Down syndrome have an extra chromosome.

Now, scientists working at the Linda Crnic Institute for Down Syndrome, based at the University of Colorado Anschutz Medical Campus, have discovered how that extra chromosome may be affecting those with Down syndrome.

The study revealed that a number of proteins involved in the immune system are hyperactive in people with Down syndrome, according to Joaquín Espinosa, executive director of the Crnic Institute and a lead researcher on the study. Their interferon response, which is supposed to target viral infections, is constantly attacking things that aren’t there.

This led the research team to determine that Down syndrome is an immune-system disorder, a “game-changing discovery,” says Michelle Sie Whitten, president and CEO of the Global Down Syndrome Foundation, which funded the study.

“It really changes the way we think about all the aspects of Down syndrome,” says Espinosa, who is also a professor of pharmacology at the university.

For example, Espinosa says, cognitive issues are often associated with those who have Down syndrome. Given the recent research, it’s reasonable to believe there could be a potential relationship between the immune system and cognitive issues.

“It really changes the way we think about all the aspects of Down syndrome."

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About 15 percent of our brain cells are part of the immune system, he says. Research has already shown that hyperactivity of these cells, called microglia, can be “toxic” to other brain cells, like neurons, which control our cognitive abilities.

The study itself, which was conducted over the course of five years on 263 people, 165 of whom had Down syndrome, was relatively simple but still “formidable,” explains Espinosa, one of eleven scientists listed on the final published study.

The researchers sought to answer the question of whether any proteins in people with Down syndrome were significantly different, meaning more or less abundant, than in those without the disorder. For example, a similar study of people with diabetes would find differences in insulin.

“By understanding what is different, you can start thinking about which of these changes can be brought back” to a healthy level, Espinosa says.

What the research team found, using technology developed by SomaLogic in Boulder, was that a large number of proteins were different in those with Down syndrome.

After looking at 4,000 proteins, they found that about 200 to 300 are statistically different, Espinosa says. Of those, about half are involved in the immune system, which led to the discovery of hyperactivity in one branch of that system.

In contrast, the part of the immune system that fights bacterial infections, called the complement system, is depleted and weakened.

The discovery could possibly explain a number of phenomena associated with those who have Down syndrome, and could open up doors for other forms of treatment and early intervention.

“When I tell you Down syndrome is an intellectual disability, it doesn't tell me anything mechanistically,” Espinosa says. “When you understand Down syndrome as an immune disorder, that changes the game in a profound way.”

Those results could help explain a number of issues that run concurrent with Down syndrome. People with Down syndrome are more likely to develop autoimmune diseases, like Type 1 diabetes, alopecia or celiac disease. They are also less likely to develop solid tumors, Espinosa says, because of the constant activity in their immune systems, while being more at risk for diseases like leukemia that cause an increase in white blood cells. Nearly 100 percent of people with Down syndrome will also develop Alzheimer’s by their forties, which could also be explained by the hyperactivity.

“Now we have a little work ahead of us” to further prove those connections and find possible treatments, Espinosa says. Researchers have already started studying the effects of drugs known as janus kinase inhibitors, or JAK inhibitors, on the inflammatory proteins in those with Down syndrome.

They have found people who were already taking the drugs for other reasons and should know those results in a few weeks, according to Espinosa. They are also studying the therapeutic effects on lab mice who have an extra chromosome, and plan to have those results within a year.

The end goal is to run a clinical trial, he adds, to test the safety and efficacy of drugs.

“By recasting Down syndrome as an immune disorder, it opens a number of doors to improve lives of Down syndrome patients with therapy,” Espinosa says, because there are already drugs on the market to temper this hyperactivity. “The question now is, would these drugs have benefits for people with Down syndrome? What are the benefits?”

While it’s clear that drugs could help with some of the autoimmune issues they’re already intended for, more research is needed to see if, for example, they could also reduce inflammation in the brain and improve cognitive function, or change the predisposition to leukemia.

The timeline for a clinical trial is harder to predict, Espinosa notes; he would be excited to finish it within the next five years.

Funding is also an issue. The most recent study was funded by the Global Down Syndrome Foundation, a nonprofit based in Denver that supports the Crnic Institute, which is the only center in the nation to exclusively focus on Down syndrome research.

“That is something we would like to change,” Espinosa says. “We would like to see the National Institutes of Health become more involved in Down syndrome research.”

Research has been underfunded, but Espinosa is hopeful that studies like this will generate more interest. He believes that many thought Down syndrome was going to disappear with pre-screening, or that it was an “intractable” issue, both of which have proved false.

The Global Down Syndrome Foundation was created to raise funds for research of the disorder, Whitten said in a statement. The nonprofit has raised between $1 million and $3 million each year since it was founded in 2009 to put toward the Crnic Institute’s studies.

While the institute has been able to make significant discoveries with philanthropic funding, Whitten said the work surrounding Down syndrome “now needs significant funding from our National Institutes of Health to take it to the next level.”

Espinosa was one of four people who presented to Congress about the state of Down syndrome research in October, and he thinks the climate is now right to ask for more funding.

“By putting funding into Down syndrome research, you’re not only serving this population, you’re also getting the opportunity to help a much larger portion of the general population,” he says.