Restoring a key hormone may help people with Down syndrome Science

Down syndrome is the most common genetic cause of intellectual disability, affecting about one in 600 babies. This happens when a person is born with an extra copy of chromosome 21, which eventually leads to distinctive physical characteristics, an increased risk of many health problems, and mild to moderate intellectual disabilities. Many people with Down syndrome are thriving—especially with access to therapy, education, and health care. But even so, researchers have been looking for drugs that could reduce 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, the researchers looked at a protein called gonadotropin-releasing hormone (GnRH). Long known as a master regulator of reproduction and widely used in fertility treatments, the hormone has recently been found to play an important role in brain development. If the neurons that secrete GnRH do not develop properly, they can cause infertility and affect the 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 young children and is critical for the formation of brain connections during adolescence.

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

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

“At that point I was very excited and thought we should try to make the leap to humans,” says Nellie Piteloud, a neuroendocrinologist at the University Hospital of Lausanne. She and Prevost teamed up for a small pilot study in seven men with Down syndrome, all between the ages of 20 and 50. 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 delivers a pulse of medication every 2 hours, mimicking the body’s natural hormone release pattern.

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 memorizing a short string of words.

Discussions about treatment, however, can cause mixed feelings in the Down syndrome community, especially when it’s presented as a disease that needs to be “cured,” says Kathleen Small, director of family services and medical outreach for the nonprofit organization Down Syndrome Connection and a mother of a child with Down syndrome. But Small says she would welcome a treatment that could make life easier for her 10-year-old son. 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 completely,” 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, believes some parents are hesitant about treatments for intellectual disabilities because there is no evidence yet that any of them work. 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 – although preliminary – are an important contribution because they open up a new avenue of research in an area that is “in dire need of new ideas”.

At the same time, high levels of certain hormones such as GnRH can also increase the risk of cancer, warns Brian Skotko of the Massachusetts General Hospital, which can be especially dangerous in people with Down syndrome, who are already at higher risk of leukemia. .

Pitteloud and Prevot are now recruiting 32 people with Down syndrome for a placebo-controlled trial of Lutrelef. Although improvements in cognitive outcomes in their preliminary trial were small, Pitteloud says parents reported seeing significant differences — for example, some found it 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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