Defense in english
Development and characterization of a new therapeutic approach of the Down Syndrome, systeme endocannabinoid
Down syndrome (DS) is the most common genetic cause of intellectual disability (ID) triggered by the complete or partial triplication of human chromosome 21 (HSA21). While researches advancements improved life conditions of patients, the ID impedes them to lead a normal life. Up to now, although several preclinical and clinical studies are ongoing, no pharmacological curative solutions that improve ID are available for patients with DS. The associated memory deficits are due to a reduction in the volume of the hippocampus (HPC) and in particular dysfunctions in GABAergic and glutamatergic transmissions. The preclinical trial failure and the lack of effective treatments for ID in DS reflect the urgent need to fine-tune a valid translational test and the primary necessity of new therapeutic targets.
The endocannabinoid system (ECS) was shown to be involved in memory and learning functions both in physiological and pathological processes. Recently, it has been suggested that the alteration of the ECS and notably the type-1 cannabinoid receptor (CB1) overexpression and hyperactivation could play a major role for ID in DS mouse models. It has been discovered that Ts65Dn aged mice expressed high levels of the endocannabinoid 2-AG in the brain and CB1 increased expression was found in Ts65Dn and TgDyrk1A mice. Giving strength to the hypothesis, the CB1 antagonist rimonabant improved memory deficits in Ts65Dn and TgDyrk1A mice. Hence, these data on DS mouse models suggesting ECS involvement in DS cognitive deficits encourage further exploration of CB1 activity deregulation.
In the team, we have recently discovered an endogenous modulatory system involving the neurosteroid pregnenolone (Preg) that counteracts the CB1 signaling activity by binding to an allosteric CB1 site, thereby blocking the toxic and addictive effects of the exogenous CB1 agonist, delta9-tetrahydrocannabinol (THC), in several animal models, thus providing a new therapeutic target for CB1-related pathologies. Although Preg has a suitable therapeutic pharmacological profile, it cannot be used as a medication, mainly due to its downstream steroid metabolism. For this reason, non-metabolized synthetic Preg analogs, named AEF compounds, were developed in collaboration with the biotech Aelis Farma and protected by patents (n° WO2019162328A1 and WO2020127468A1). AEF compounds maintain the pharmacological properties of Preg against CB1 but with an upgraded and further strengthened therapeutic profile. Indeed, AEF compounds have an increase half-life, are not metabolized in steroid hormones and have a very good bioavailability after oral administration. In the thesis work, the AEF0217 compound was studied as a leader candidate for the treatment of ID in DS.
The general objectives of this thesis were:
1) Investigation of the neurobiological bases underlying the ID in DS;
2) Validation of a translational test for the evaluation of ID in DS patients and trisomic Ts65Dn mice;
3) Proposition of a therapeutic solution for ID in DS.
The current work confirmed that the ECS played a key role in ID in Ts65Dn mice. 1) Key elements highlighted an overexpression of CB1 in specific region and cell populations of the dorsal HPC and decreased levels of Preg and Preg synthesis encoding enzyme gene Cyp11a1. Preg rescued synaptic plasticity and memory deficits. Furthermore, inhibition of CB1-induced Erk1/2MAPK activity restored memory impairment in Ts65Dn mice. 2) We then validated the Radial-maze procedure as a suitable translational test for the assessment of ID in DS providing the basis for a novel therapeutic approach with preclinical and clinical significance. 3) Finally, the Preg-like compound AEF0217 also rescued cognitive deficits in several cognitive tests, including the translational Radial-maze test in Ts65Dn mice. In conclusion, the therapeutic profile of AEF0217 associated with the translational test constitutes promising assets towards a clinical application.
Silvia-Gines Padros, Professor; Neuroscience Institute, University of Barcelona, SP – Reviewer
Marie-Claude Poitier, PharmD, PhD; Institut du cerveau of Paris, FR – Reviewer
Yann Herault, PhD; IGBMC Institute, Strasbourg, FR – Examiner
Filippo Caraci, Professor, MD, PhD; Neuroscience Institute, University of Catania, IT – Examiner
Monique Vallée, PhD; Neurocentre Magendie, Bordeaux, FR – Guest
Jean-Michel Revest, PhD; Neurocentre Magendie, Bordeaux, FR – Supervisor
Nadia di Franco
Thesis supervisor: Jean-Michel Revest