Mutuelles AXA TND-UPS : Stéphane Bézieau (2023 - 2026)
Stéphane Bézieau is the scientific leader of a mutual AXA project entitled : Identification of therapeutic targets using brain organoids to treat neurodevelopmental disorders caused by dysfunction of the ubiquitin-proteasome system (TND-UPS)
The long-term objectives of our project are to improve the diagnosis of TND-UPS and to identify drugs that can significantly improve the health of patients and/or have a positive effect on the course of the disease.
Our first objective at the end of the project is therefore to set up simple tests that can be routinely applied in molecular genetics laboratories, based on the specific biomarkers of TND-UPS that we will have identified.
The early diagnosis of the disease made possible by these tests will enable patients to break the diagnostic deadlock in which they have often found themselves for years. It will also be possible to monitor the biological evolution of the disease and adapt care accordingly.
And we hope that this care will be based in particular on effective drugs, which are the ultimate goal of our project. We don't yet know what effect they will have on the neurological signs that have already set in, but we do know that they will be crucial to the quality of life and life expectancy of patients. We do not have sufficient hindsight to reliably predict how TND-UPS develops with age, but our knowledge of UPS in general suggests that patients suffering from TND-UPS may be predisposed to certain forms of cancer, or even neurodegenerative diseases in later life.
Summary
TND-UPS are neurodevelopmental disorders (NDD) caused by mutations in genes of the ubiquitin-proteasome system (UPS), a set of 1,200 enzymes that protect the body's cells against toxic accumulations of proteins. To understand how TND-UPS function, we will be analysing mini-brains produced from patients' stem cells. Our aim is to identify therapeutic targets to offer hope of treatment to sick children.Objectives
TND-UPS represent a significant group of rare diseases, with around 1,200 genes involved in UPS, all of which are potential candidates for TND. However, because the pathophysiology of TND-UPS is poorly understood, diagnosis is severely delayed and prevents appropriate follow-up. Similarly, no treatment - or even preclinical trial - is currently available for TND-UPS.The long-term objectives of our project are to improve the diagnosis of TND-UPS and to identify drugs that can significantly improve the health of patients and/or have a positive effect on the course of the disease.
Our first objective at the end of the project is therefore to set up simple tests that can be routinely applied in molecular genetics laboratories, based on the specific biomarkers of TND-UPS that we will have identified.
The early diagnosis of the disease made possible by these tests will enable patients to break the diagnostic deadlock in which they have often found themselves for years. It will also be possible to monitor the biological evolution of the disease and adapt care accordingly.
And we hope that this care will be based in particular on effective drugs, which are the ultimate goal of our project. We don't yet know what effect they will have on the neurological signs that have already set in, but we do know that they will be crucial to the quality of life and life expectancy of patients. We do not have sufficient hindsight to reliably predict how TND-UPS develops with age, but our knowledge of UPS in general suggests that patients suffering from TND-UPS may be predisposed to certain forms of cancer, or even neurodegenerative diseases in later life.
Innovative character
The study we are proposing is the first to compare mini-brains carrying variants identified with recurrence in children suffering from TND caused by a loss of function of the UPS. In terms of technology, this project will use cutting-edge methods: genome editing to obtain pluripotent stem cell lines differing by only one nucleotide; in vitro generation of brain organoids derived from these lines, faithfully recapitulating the tissue abnormalities in the brains of children affected by TND-UPS - the best hopes rest on organoids for predicting therapeutic responses in humans, given the failure of animal models in this field; the analysis of proteasomes and ubiquitinylomas using modern mass spectrometry techniques proven on organoids; the impact of UPS dysfunction on neurogenesis assessed using the latest real-time imaging methods.
Updated on 01 September 2025.