Treating Neurodevelopmental Disorders Caused by Ubiquitin-Proteasome System Dysfunction with Therapeutic Targets Using Brain Organoids

Neurodevelopmental disorders (NDDs) affect more than 3% of children worldwide. About 5–7% of these, TND-UPS, are caused by mutations in genes in the ubiquitin-proteasome system (1200 genes in total). The UPS system normally participates in protein homeostasis by degrading proteins for recycling. Since 2017, we have identified more than 250 mutations in 30 UPS genes in TND-UPS children and built a unique biocollection (BioTND-UPS) of 300 blood cell samples from children and their healthy parents. 

The project led by Stéphane Bezieau aims to better understand the group of severe rare diseases that constitute the TND-UPS. Poorly diagnosed due to a lack of specific biomarkers and no available treatment, TND-UPS leaves patients without a solution for years. The objectives are to identify (i) specific biomarkers allowing early diagnosis, personalized follow-up and better clinical management; and (ii) therapeutic targets paving the way for the development of effective treatments, in order to improve the quality and life expectancy of patients and reduce the socio-economic impact of NSD-UPS. 

The project innovates by reproducing in vitro the specific neuronal alterations of patients with TND-UPS, a group of rare neglected diseases, using genetically edited brain organoids. The approach thus illustrates the notion of personalized medicine towards which health professionals are striving, by identifying targeted therapies based on the morphological, cellular and molecular characteristics of mutated cells.