Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and autism, affecting millions of people worldwide. While many treatments have been explored, no single therapy effectively addresses all of the challenges caused by the condition.
From 2021 to 2023, FRAXA Research Foundation funded a research grant at Stanford University to investigate how different drug combinations could help improve brain function in FXS. Led by Dr. Philippe Jacques Mourrain, Dr. Gordon Wang, and FRAXA Fellow Dr. Rochelle Coulson, the study aimed to identify treatments that could restore normal function and behavior at the synapses of neurons.
One of the most promising findings from this research was that an experimental drug ISRIB (Integrated Stress Response Inhibitor) has potential to improve brain function and social behavior in a Fragile X mouse model.
ISRIB and Its Impact on Fragile X Syndrome
ISRIB is a drug that influences how cells handle stress and regulate protein production. In FXS, neurons struggle to properly manage proteins, which disrupts learning, memory, and social behavior. By reducing the activation of the integrated stress response (ISR) — a cellular stress pathway that becomes overly active in Fragile X — ISRIB helps restore more normal brain function.
Researchers tested ISRIB in Fmr1 knockout (KO) mice, a well-established model of Fragile X. The results were encouraging:
Healthier Brain Structure
Fragile X brain neurons tend to have too many immature dendritic spines, which interferes with proper brain communication. ISRIB reduced the number of these immature spines, making neural connections more efficient.
Stronger Synaptic Function
Synapses, the connections between brain cells, were better able to communicate after ISRIB treatment. The drug increased levels of GluA1, a key receptor that supports brain signaling and plasticity.
Improved Social Behavior
ISRIB helped Fragile X mice recognize and interact with new social partners, a skill often impaired in individuals with FXS.
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These findings highlight the potential of targeting underlying protein regulation issues in Fragile X syndrome. One of the greatest challenges in treating Fragile X has been finding a way to correct multiple brain problems at once. This study suggests that ISRIB might be able to do exactly that — by restoring balance in the way neurons handle protein production.
What’s Next for ISRIB?
While ISRIB has not yet been tested in humans for Fragile X, researchers are continuing to study its effects in other conditions, including traumatic brain injury (TBI) and neurodegenerative diseases.
A 2022 study from the University of California, San Francisco (UCSF) found that ISRIB could also reverse cognitive damage caused by concussions. The research showed that brain injuries often trigger an overactive ISR, leading to excessive dendritic spine growth — similar to what is seen in Fragile X. When ISRIB was administered to mice with brain injuries, their brain function improved and their synaptic connections returned to normal.
Early-stage human trials are already underway to test ISRIB for safety and effectiveness in treating brain injuries and neurodegenerative diseases such as Alzheimer’s and Parkinson’s. If successful, these studies could pave the way for future trials in Fragile X syndrome.
Explore Explore the Full Research Findings
These findings were published in iScience in the article: "Translational modulator ISRIB alleviates synaptic and behavioral phenotypes in Fragile X syndrome".
FRAXA remains committed to funding innovative research aimed at improving treatments for Fragile X syndrome. Stay connected for updates on the latest advancements!
Written by
Anna Devine graduated from Wake Forest University in 2023 and currently works as a patient coordinator at a fertility clinic in New York City. She is working towards a career in genetic counseling, and discovered FRAXA after learning more about Fragile X from research, podcasts, and stories from current genetic counselors. She would love to work with Fragile X individuals and carriers in her career as a genetic counselor later on!
