UCLA Health researchers have identified a potential drug target for treating Fragile X syndrome, the most common genetic cause of intellectual disability and autism that affects roughly 1 in 2,000 boys.
Fragile X syndrome is caused by a mutation in a single gene, FMR1, that results in the loss of a protein critical for normal brain development and function. People with the condition commonly experience intellectual disability, difficulty with attention and social interaction, heightened sensitivity to sensory input such as sound and touch, and a higher risk of seizures. Many also meet the criteria for an autism spectrum disorder diagnosis.
As it is caused by a change in a single gene, Fragile X has long been considered a promising candidate for targeted therapies yet clinical trials to date have not produced an effective treatment.
In the new study published in Neuron, researchers used genetically engineered mice that are missing the FMR1 gene to simulate Fragile X syndrome. Using genetic sequencing, they found that levels of the gene EPAC2 were increased in the brain of Fragile X mice. This was of potential interest as a target for therapy because the protein, also called EPAC2, is localized to synapses and is known to be important for learning and memory. The researchers then demonstrated that blocking EPAC2 in the Fragile X mouse model restored abnormal patterns of brain activity and improved several behavioral symptoms associated with Fragile X syndrome including heightened sensitivity to touch, difficulties with social interaction and their susceptibility for seizures.
“EPAC2 emerged as an attractive target because it was consistently altered across multiple types of brain cells in our analysis,” said the study’s lead author Dr. Anand Suresh, a post-doctoral fellow in the laboratory of Dr. Carlos Portera-Cailliau, professor of neurology at UCLA and member of the UCLA Brain Research Institute. “When we blocked it, either genetically or with a drug compound, we saw meaningful improvements in both brain circuit function and behavior.”
EPAC2 is expressed almost exclusively in the brain, which means drugs targeting it are less likely to cause unwanted effects elsewhere in the body. Suresh said this is an important consideration as researchers continue preclinical studies.
To reach this finding, UCLA researchers used an RNA sequencing technique to examine gene activity separately in two major classes of brain cells: those that excite and those that inhibit neural activity. Fragile X syndrome is thought to arise from an imbalance between these two systems. The analysis revealed striking differences in how the genetic mutation underlying Fragile X syndrome affects each cell type but also identified a small set of genes, including the one that encodes EPAC2, that were dysregulated in both.
The researchers also found that EPAC2 levels appear to rise gradually as the brain matures, suggesting it may be a particularly relevant target for older children and adults with Fragile X syndrome, rather than only in early development.
