Cognitive abilities of patients with trisomy 21 improved by promising therapy

the syndrome from Down, or Trisomy 21is a chromosomal abnormality which concerns approximately one in 800 babies in France. Human chromosomes are organized into 23 pairs, but people with trisomy 21 carry three copies of chromosome 21, the smallest of them all. This results in a wide range of symptomsincluding a decline in cognitive functions with age, but also a decrease inolfaction.

A team from the Lille neuroscience and cognition laboratory, attached to Inserm, and the Vaudois University Hospital Center of Lausanne in Switzerland have collaborated to test the effectiveness of a therapy based on GnRH (Gonadotropin-Releasing Hormone or pituitary gonadotropin-releasing hormone) aimed at improving the cognitive functions of a small group of patients with trisomy 21. The results appeared in Science.

Positive results in mice…

GnRH is synthesized by neurons and regulates reproductive functions via I’hypothalamus, but not only. Recent discoveries suggest that the hormone acts in other regions of the brain involved in cognitive tasks in particular. With this observation in mind, the research group of Vincent Prévot, Inserm research director at the Lille neuroscience and cognition laboratory, conducted experiments on model mice for trisomy 21. rodentchromosome 16 gate exactly the same genes as human chromosome 21, so it is the latter that is present in three copies.

The scientists thus demonstrated that microRNAs, whose role was to activate or inactivate the synthesis of GnRH, no longer fulfilled their role. Indeed, they are located on chromosome 16 in mice (and chromosome 21 in humans), and the presence of a third copy causes abnormalities in the neurons secreting GnRH, which deregulates the production of the hormone. . The olfactory and cognitive deficiencies observed in mice could be corrected thanks to the injection of GnRH, at levels comparable to those observed in wild mice.

…and in patients with trisomy 21

These results were discussed with Nelly Pitteloud, professor at the Faculty of Biology and Medicine at the University of Lausanne and head of the Department of Endocrinology, Diabetology and metabolism from CHUV. His team specializes in diagnostic of a rare congenital deficiency of GnRH, depriving the persons concerned of spontaneous puberty. To induce puberty, the latter receive pulsatile subcutaneous injections of GnRH to reproduce the natural behavior of the hormone.

The effectiveness of this treatment has been tested on patients with trisomy 21 — 7 in all, men aged 20 to 50 who received a physiological dose of GnRH every two hours for six months. A pilot study which provided promising results: at the end of the treatment, the cognitive performance of the patients improved; these were accompanied by a change in functional connectivity observed by MRI.

On the other hand, no benefit was observed on olfaction. ” Maintenance of the GnRH system appears to play a key role in brain maturation and cognitive function “, explains Vincent Prévot. ” In trisomy 21, pulsatile GnRH therapy is promising, especially since it is an existing treatment and without significant side effects. “, adds Nelly Pitteloud.

The beginnings of a larger study

The collaboration between the two teams continues this fall with the launch of a larger study, ideally including 60 people with trisomy 21, including women, and a control group, which will determine whether the benefits observed are not due to the effect placebo. If the results are exciting, they are not sufficient to justify a prescription of GnRH to patients with Down syndrome, said Nelly Pitteloud during a press conference.