On the occasion of world trisomy 21 day, on March 21, 2016, the ICM reviews the work conducted by Marie-Claude Potier’s team on this pathology.
Trisomy 21 is a chromosomal disorder defined by the presence of a third copy, in whole or in part, of chromosome 21. In France, 1 child out of 1400 is born with this pathology. The disease manifests itself, among other things, by intellectual impairment and learning and memory deficits which vary between individuals.
In order to treat intellectual disability in trisomy 21, current research is oriented towards two major directions :
- modulate the dysregulated genes of chromosome 21, either directly or by modification of the activity of proteins synthesized by these genes ;
- act on the problems observed at the level of brain neurotransmitters.
A GENE INVOLVED IN TRISOMY 21 AND ALZHEIMER’S DISEASE
Chromosome 21 is the smallest of our chromosomes, it contains 364 genes, some of which are involved in Alzheimer’s disease, including DYRK1A gene. People with trisomy 21 have a higher risk of declaring Alzheimer’s disease. When they are aged 60, about 45% of people with trisomy 21 have Alzheimer-type dementia. In these patients, an overexpression of DYRK1A protein in the brain had been demonstrated. Jean Delabar, in Marie-Claude Potier’s team, has showed that this protein is also overexpressed in the brain of patients with Alzheimer’s disease. This protein could therefore be used as early marker and as a risk factor for Alzheimer’s disease. In collaboration with Bruno Dubois, trials are underway in the INSIGHT cohort to detect whether variation of this protein appears before pathology and could therefore be, in addition, a predictive marker of the disease.
Moreover, Marie-Claude Potier’s team is trying to elucidate molecular and cellular mechanisms leading to cognitive deficits in order to implement new therapeutic strategies to combat them.
ACT ON NEUROTRANSMITTERS : A PHASE 2 ONGOING CLINICAL TRIAL
Marie-Claude Potier’s team has shown for the first time, in 2011, the therapeutic effects of a molecule which blocks the effect of the GABA neurotransmitter in a trisomy 21 mouse model (an inverse agonist of alpha5 GABA receptor). GABA is a neurotransmitter, i.e. a molecule that allows neurons to communicate between them. In the brain of individuals with Trisomy 21, there is an excess of GABA. By reducing the excessive GABA, this molecule improves brain functioning and restores cognitive deficits. This molecule is currently the subject of a phase II clinical trial conducted by Hoffmann la Roche.
Marie-Claude Potier’s team has also an ongoing project, in collaboration with Alberto Bacci’s team, to understand the mechanisms involved at the level of GABAergic neurons.
For further information : find the international research society on trisomy 21’s website , from which Marie-Claude Potier is Secretary General.