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Restoring a key hormone could help people with Down syndrome

New research with mice—and a small human trial—raises the prospect of treatments that could improve learning difficulties in people with Down syndrome. Though still preliminary, the work may represent a step toward a goal that has eluded scientists for decades.

Down syndrome is the most common genetic cause of intellectual disability, affecting about one in 600 babies. It occurs when a person is born with an extra copy of chromosome 21, ultimately leading to distinctive physical features, an elevated risk of many health problems, and mild to moderate intellectual impairments. Many people with Down syndrome thrive—especially with access to therapy, education, and health care. But researchers have nevertheless sought drugs that could lessen the learning and communication differences and help more people with Down syndrome live on their own. Although many drugs have shown promise in mice, none of the candidates have improved cognition in human trials.

In the new study, researchers looked at a protein called gonadotropin-releasing hormone (GnRH). Long known to be a master regulator of reproduction and widely used in fertility treatments, the hormone has been found more recently to play an important role in brain development. If neurons that secrete GnRH don’t develop properly, they can cause infertility and interfere with sense of smell, both of which can affect people with Down syndrome. GnRH also influences the development of language and other cognitive abilities in infants and toddlers, and is critical for the formation of brain connections during adolescence.

Vincent Prevot, a neuroendocrinologist at the University of Lille, wondered whether low GnRH levels during early development might play a similar role in Down syndrome. To find out, he and his team ran a series of experiments with mice that had been genetically engineered to make an extra chromosome similar to the one in Down syndrome. They tested the rodents’ memory and sense of smell as they aged and found both got worse after puberty. The mice also had abnormalities in their GnRH-secreting neurons, caused by disrupted regulation of genes located on chromosome 21, the team found. Many cells “were empty” of GnRH by the time the rodents were young adults, Prevot says.

The team was able to restore GnRH production in the cells using microRNAs—strands of RNA that act as switches for gene expression—and reverse the rodents’ smell and memory deficits. When they gave Lutrelef, a drug commonly used to replace GnRH in people, to the Down syndrome mice their ability to remember different objects and distinguish between smells matched those of the healthy mice after 2 weeks of treatment, the team reports today in Science.

“At this point, I was very excited and thought we should try the jump to humans,” says Nelly Pitteloud, a neuroendocrinologist at the Lausanne University Hospital. She and Prevot teamed up for a small pilot study in seven men with Down syndrome, all between 20 and 50 years old. The participants and their legal guardians consented to the study, which involved receiving Lutrelef through a small needle and pump taped to their upper arms. The pump delivered a pulse of the drug every 2 hours, mimicking the pattern of how the hormone is naturally released in the body.

After 6 months, the men showed a 10% to 30% improvement on the Montreal Cognitive Assessment, a standard measure of intellectual disability. The test challenges spatial and verbal memory with tasks such as drawing a 3D cube or remembering a short string of words.

Discussions of treatment can elicit mixed feelings in the Down syndrome community, however, especially when it’s framed as a disease that needs to be “cured,” says Cathleen Small, a director of family services and medical outreach for the nonprofit Down Syndrome Connection and mother of a child with Down syndrome. But Small says she’d welcome a treatment that could make her 10-year-old son’s life easier. Improving someone’s memory or communication skills isn’t likely to change their personality, she says, just improve their quality of life. “Where it gets problematic is when people talk about eliminating Down syndrome altogether,” she says. Prenatal testing for Down syndrome has led to a sharp decline in the number of children born with the condition in many countries, including the United States.

Alberto Costa, a neuroscientist at Case Western Reserve University, thinks some parents are hesitant about treatments for intellectual disability because there’s no evidence any of them work yet. Costa, whose 27-year-old daughter has Down syndrome, is still struggling to understand why his own group’s large clinical trial of the Alzheimer’s drug memantine failed in people with Down syndrome—a crushing blow after more than a decade of promising preclinical data. He says the new GnRH findings—though preliminary—are an important contribution because they open up a fresh avenue of research in a field that “badly needs new ideas.”

At the same time, high levels of some hormones like GnRH could also increase cancer risk, Massachusetts General Hospital’s Brian Skotko cautions, which could be especially dangerous in people with Down syndrome, who are already at higher risk of leukemia.

Pitteloud and Prevot are now recruiting 32 men and women with Down syndrome for a placebo-controlled trial with Lutrelef. Although the improvements in cognitive scores in their preliminary trial were small, Pitteloud says parents reported seeing meaningful differences—for example, some found it was easier to talk to their sons on the phone. Others noticed improvements in attention span and memory that could help with everyday tasks like navigating a city, Pitteloud says. “The real goal is to see improvement in everyday life.”

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