Targeting Cell Type-Specific Protein Dysregulation in FXS-Patient Derived Brain Organoids with FMR1 Methylation Mosaicism
Nicola Elvassore, PhD
Principal Investigator
Carmela Ribecco, PhD
FRAXA Postdoctoral Fellow
Martina D’Ercole, PhD
Postdoctoral Fellow
University of Padua
Padua, Italy
2025-2026 Grant Funding: $100,000
Supported through FRAXA’s Curative Therapies Fund
Summary
Fragile X results from silencing of the FMR1 gene, but not all cells are affected equally — some still produce a little protein, a condition called mosaicism. Using stem-cell–derived brain organoids, researchers in Padua found that full silencing disrupts synapses, while partial silencing alters metabolism and cell growth. These findings suggest that tailored or combination therapies may be needed to restore brain function in Fragile X. This project could guide the development of personalized therapies for Fragile X.
The Science
by Nicola Elvassore
Fragile X syndrome (FXS) is caused by a mutation in the FMR1 gene, which becomes abnormally silenced in affected individuals. However, not all patients have the same pattern of gene silencing; some cells show different levels of FMR1 transcription and translation, a phenomenon known as mosaicism.
We use advanced stem cell technology to recreate early human brain development in the lab. This allows us to study how mutated FMR1 is switched off at different stages and how this impacts the proteins needed for brain function and connections. We discovered that the gene silencing happens earlier than previously thought, and in some cases, FMR1 remains partially active, potentially explaining the variability of phenotypes seen in patients.
By examining the growth of organoids (small 3D brain-like structures derived from pluripotent stem cells), we found that protein imbalances differs among cell types, with distinct dysregulation patterns depending on the extent of FMR1 silencing. In cases of full silencing (full methylation), the disruption primarily affects neuronal synapses, whereas in unmethylated condition, it impacts cell metabolism and proliferation.
Understanding these differences is crucial for developing more effective treatments. Current therapies often focus on a single molecular target, which has shown limited success. Our studies suggest that a combined approach targeting multiple aspects of Fragile X syndrome could be more effective in restoring brain function.