Carlos Portera-Cailliau, MD, on EPAC2 as potential therapeutic target in Fragile X syndrome

Researchers at UCLA Health have identified a potential therapeutic target for Fragile X syndrome, a genetic neurodevelopmental disorder associated with intellectual disability, autism spectrum disorder, seizures, and sensory hypersensitivity.¹

The findings, published in Neuron, identified the protein EPAC2 as a possible treatment target after researchers demonstrated that reducing its activity in a mouse model of Fragile X syndrome improved both brain circuit abnormalities and behavioral symptoms.

Fragile X syndrome is caused by mutations in the FMR1 gene, resulting in loss of the fragile X messenger ribonucleoprotein (FMRP), which is critical for normal brain development and synaptic function. Although Fragile X syndrome has long been considered a candidate for targeted therapies because it is caused by a single-gene mutation, previous clinical trials have not produced approved disease-specific therapies.²

Researchers used genetically engineered mice lacking the FMR1 gene to model Fragile X syndrome and performed RNA sequencing to examine gene activity in excitatory and inhibitory neurons. The analysis showed that gene dysregulation differed substantially between the 2 cell types, but EPAC2 was consistently increased in both.

“EPAC2 is a target that we found in an unbiased screen for gene dysregulation in Fragile X mice,” said Carlos Portera-Cailliau, MD, PhD, professor of neurology and neurobiology at UCLA. “The gene expression studies pointed to EPAC2 as being the only gene that was dysregulated both in excitatory and inhibitory neurons.”

How did blocking EPAC2 affect Fragile X symptoms in mice?

Researchers noted that EPAC2 is highly enriched in the brain, which may reduce the likelihood of systemic adverse effects if therapies targeting the protein are eventually developed.

“Other genes and proteins might be expressed all over the body, but EPAC2 is very enriched in the brain,” Portera-Cailliau said.

The investigators reported that reducing EPAC2 activity restored abnormal brain activity patterns and improved several Fragile X–associated behaviors in mice, including susceptibility to seizures, memory deficits, sensory hypersensitivity, and social interaction abnormalities.

“When we reduced the levels of EPAC2, we found that it rescued not just circuit differences in the brains of Fragile X mice, but also multiple behavioral deficits in the mice,” Portera-Cailliau said.

The study also explored the role of excitatory and inhibitory imbalance in Fragile X syndrome and other neurodevelopmental disorders. Researchers found that loss of FMRP affected the 2 neuronal populations differently, which may contribute to abnormal neural signaling.

“One of the long-standing theories of autism and other neurodevelopmental conditions is that there is an imbalance between excitation and inhibition in the brain,” Portera-Cailliau said.

Could EPAC2 therapies help older children and adults with Fragile X syndrome?

The researchers suggested that sensory hypersensitivity may represent a particularly relevant area for future clinical translation. According to Portera-Cailliau, tactile defensiveness improved after EPAC2 inhibition in the mouse model.

“A majority of boys with Fragile X experience sensory hypersensitivity, particularly to tactile stimuli,” he said. “The fact that this drug rescued a lot of the aversion to repeated whisker stimulation might potentially translate to improving sensory hypersensitivity in children with Fragile X.”

Investigators also observed that EPAC2 overexpression appeared more pronounced in adult Fragile X mice than in younger mice. The finding may have implications for treatment timing.

“EPAC2 is upregulated in adult Fragile X mice, and we intervene by inhibiting it, and could rescue a lot of phenotypes in adult mice, suggesting that potentially it could be a mechanism for intervention in older children and adults who live with Fragile X,” Portera-Cailliau said. “It is never too late to intervene in this disease.”

Although the findings remain preclinical, researchers said the study contributes to ongoing efforts to identify targeted therapies for Fragile X syndrome following multiple unsuccessful clinical trials.

“The main message is renewed hope,” Portera-Cailliau said. “There’s a lot of really smart people working in the labs around the world to discover new treatments for fragile X.”

Disclosure: Portera-Cailliau reports no relevant disclosures.

References

1. Houston W. New drug target identified for Fragile X syndrome. UCLA Health. May 18, 2026. Accessed May 28, 2026. https://www.uclahealth.org/news/release/new-drug-target-identified-fragile-x-syndrome

2. Cleveland Clinic. Fragile X Syndrome (FXS). Cleveland Clinic. Updated February 7, 2024. Accessed May 28, 2026. https://my.clevelandclinic.org/health/diseases/5476-fragile-x-syndrome