Therapy with the gonadotropin-releasing hormone GnRH could possibly reduce cognitive impairments in people with Down syndrome. In a mouse model, researchers discovered that some symptoms of Down syndrome may be due to an abnormal release of this hormone. An already established therapy for people with GnRH deficiency improved cognitive functions both in a mouse model and in a pilot study with seven Down syndrome patients. Larger clinical studies are now to further evaluate the benefit.
Down syndrome, also known as trisomy 21, occurs in about 1 in 800 live births, making it the most common genetic cause of intellectual disability. The cause is an additional chromosome 21. In addition to various physical symptoms, those affected usually have significantly reduced cognitive abilities. In addition, many develop Alzheimer’s-like symptoms in adulthood. Another symptom is the gradual loss of smell, which often begins in prepuberty. While many women with Down syndrome can have children, most affected men are infertile.
Trisomy 21 disrupts hormone production
A team led by Maria Manfredi-Lozano from the University of Lille in France has now researched a possible therapy for some symptoms of Down syndrome. “The loss of the sense of smell, combined with infertility, are also typical symptoms of patients with a congenital deficiency of gonadotropin-releasing hormone (GnRH), the so-called Kallmann syndrome,” explain the authors. GnRH is released by specialized neurons in the hypothalamus and is primarily responsible for triggering the production of certain reproductive hormones. However, new studies also indicate that it could also have an influence on higher brain functions.
The similarities in symptoms in Kallmann syndrome and Down syndrome prompted researchers to look more closely at the role of GnRH in Down syndrome. To do this, they first worked with a mouse model that mimics the changes resulting from trisomy 21. In fact, they came across a mechanism that explains why GnRH is a problem in people with Down syndrome: the production of the hormone is regulated by so-called microRNAs. At least five of these microRNAs are encoded by regions on human chromosome 21 – and are therefore disrupted in people who have three copies of this chromosome.
Promising results in mice
In Down syndrome mice, Manfredi-Lozano and her team demonstrated that it is actually GnRH deficiency that contributes to cognitive impairment, loss of smell and impaired sexual maturation in the animals. If the researchers gave the mice GnRH regularly or implanted cells that correctly produced the hormone, the symptoms were alleviated. After just 15 days of treatment, the mice showed improved cognitive function and also regained their sense of smell. However, the animals did not become fertile as a result of the treatment.
“Because of the convincing results in mice, we carried out a pilot study in human Down syndrome patients as a next step,” the researchers write. They used a form of therapy that is already established for the treatment of Kallmann syndrome: the patients have a small pump transplanted under the skin on their arm, which administers a small dose of GnRH every two hours. This so-called pulsatile GnRH therapy mimics the natural release of the hormone in the body.
Larger clinical trials needed
Seven men with Down syndrome between the ages of 20 and 50 received this therapy for six months. Before and after, the researchers tested their cognitive abilities and their sense of smell and also performed MRI scans. The result: after six months of therapy, six out of seven patients were able to understand instructions better, solve logic tasks better, were more attentive and had an improved episodic memory. MRI scans also showed that functional connectivity in the brain had increased. Unlike the mice, however, the treatment had no effect on the patients’ sense of smell.
“Pulsatile administration of GnRH appears to be a promising approach, with few anticipated side effects, to improve cognitive function in a broad spectrum of cognitive decline disorders characterized by impaired function of GnRH neurons,” writes Hanne Hofmann from Michigan State University in a commentary accompanying the study, also published in the journal Science. “To fully determine the value of pulsatile GnRH in improving cognitive function, a randomized controlled trial that includes both sexes is needed.” Women were not included in the pilot study because GnRH can disrupt their menstrual cycle. “However, in women who are past reproductive age or who do not wish to conceive, pulsatile GnRH treatment is likely to be just as beneficial as in men for improving cognitive performance,” said Hoffmann.
Quelle: Maria Manfredi-Lozano (University of Lille, Frankreich) et al., Science, doi: 10.1126/science.abq4515