People with trisomy 21 – about one in 800 births – have an extra chromosome. And this supernumerary chromosome has a characteristic that would explain one of the clinical manifestations of the disease: cognitive decline. However, this could be improved thanks to a therapy successfully tested by scientists from Inserm (Lille) and the Center hospitalier universitaire vaudois (Lausanne) on a small group of people with trisomy 21.
The researchers proceeded in several steps, described in the review Science. The team from the Lille neuroscience & cognition laboratory (Inserm/University of Lille/CHU of Lille) first started with a recent discovery concerning the neurohormone GnRH, involved in the onset of puberty and fertility. It has recently been known that it also plays a role in the maintenance of cognitive function. The researchers therefore used mice genetically modified to reproduce human trisomy, in order to study the mechanism of regulation of GnRH in this context.
Neuronal abnormalities
They discovered that five microRNA strands involved in the production of this hormone and present on chromosome 21 were deregulated. In other words, in the mouse model of trisomy 21, abnormalities are observed in the neurons secreting GnRH. And these lead to progressive cognitive impairment.
Is it irreversible or is it possible to reverse the trend? This is where the doctors from the Vaud University Hospital Center come in, specialists in the treatment of congenital GnRH deficiency, a rare disease that manifests itself by an absence of spontaneous puberty in adolescents. The treatment, which consists of injecting GnRH by reproducing the natural pulsatile rhythm of the secretion of this hormone, was tested in the mouse model of trisomy 21 in order to see if it could act on cognitive function.
With success, since in just 15 days of treatment similar to the protocol planned for humans, the team demonstrated a restoration of cognitive functions in mice. And decided to take the next step: testing the effectiveness of the treatment in humans. A pilot clinical trial was therefore conducted on seven men with trisomy 21, aged 20 to 50 years.
6 out of 7 patients
Each of the participants received a dose of GnRH every two hours subcutaneously for 6 months, using a pump placed on the arm. At the end of the trial, the cognition tests showed an improvement in performance in 6 of the 7 patients: better three-dimensional representation, better understanding of instructions, improvement in reasoning, attention and episodic memory. Visible changes on MRI.
These results suggest that pulsatile GnRH therapy produces effects on the brain, in particular by strengthening communication between certain regions of the cortex, which makes it possible to improve cognitive function. This therapy is therefore promising, and not only for people with trisomy 21: certain neurodegenerative pathologies, including Alzheimer’s disease, are potentially concerned. Provided of course that the treatment is validated on a larger scale, and including women.