METTL3 Inhibitors to Address Neurodevelopmental Defects in Fragile X Syndrome: Insights from Patient-Derived 3D Brain Organoids
Ziyuan Guo, PhD
Principal Investigator
Lu Lu, PhD
FRAXA Postdoctoral Fellow
Cincinnati Children's Hospital
Cincinnati, OH
2025-2026 Grant Funding: $100,000
Summary
This research explores a new and promising approach to Fragile X by targeting RNA — specifically, a chemical tag called m6A that controls how brain cells use genetic instructions.
By blocking an overactive enzyme called METTL3, researchers hope to restore normal brain cell function using both lab compounds and FDA-approved drugs. If successful, this work could uncover a new pathway for treatment and shorten the road to potential therapies.
The Science
Regulation of messenger RNA (mRNA) plays an important role in how brain cells function. One key chemical tag on mRNA, called m6A (N6-methyladenosine), helps control which proteins are made and when. In Fragile X syndrome, the absence of FMRP disrupts this process and causes an enzyme called METTL3 to become overactive. This leads to too many m6A tags on mRNA, which can interfere with gene expression and communication between brain cells.
Researchers have found that blocking METTL3 activity can help restore more normal gene regulation in neurons grown from the cells of individuals with Fragile X. To explore this further, the team will use 3D brain organoids, miniature brain models made from patient cells, to study how m6A regulation affects different types of brain cells, including neurons, astrocytes, and neural progenitor cells.
They will test three compounds that inhibit METTL3: STM2457, a laboratory compound, and two FDA-approved drugs, elvitegravir and eltrombopag, that may be repurposed for Fragile X.
By targeting m6A regulation, this research could uncover a new pathway involved in Fragile X syndrome and point to drug candidates that may move more quickly toward clinical evaluation.