The Prospect of a New Treatment for Fragile X Syndrome


A team from the Institute of Molecular and Cellular Pharmacology (Valbonne – Sophia Antipolis), led by Inserm researcher Barbara Bardoni, has revealed the key role of a protein, PDE2A, in the development of Fragile X syndrome. A discovery that opens up the possibility of identifying new treatments in the near future.

Bardoni and her team have been working on Fragile X syndrome (FXS) for over twenty years. This genetic disease affects around one in 4,000 men and one in 8,000 women. It is the most common form of hereditary intellectual disability, and one of the leading genetic causes of autism spectrum disorders. At present, there is no specific treatment to manage the disease.

FXS is caused by loss of expression of the FMR1 gene, which results in absence of the protein Fragile X Mental Retardation Protein (FMRP). This protein plays an important role in the production and transport of other molecules into neurons.

As a result of their work, the researchers have been able to identify certain prominent targets of FMRP, and have improved understanding of how the disease evolves over time.

An FXS murine model for conducting experiments

The researchers worked on murine models of the syndrome, which allowed them to study defects in the central nervous system, and the social communication disorders observed in patients. They focused on a critical period of brain development, around the 13th day of life, and on specific areas of the brain, in particular the hippocampus, cerebral cortex, and cerebellum. “The neurons of patients with FXS have abnormal synapses. More specifically, their dendritic spines are immature, too long or too thin. The 13th day of life is the moment when the synapses and dendritic spines form in the brains of mice, and when expression of the FMRP protein is at its maximum level,” explained Bardoni.

An initial series of experiments showed that one of the targets of FMRP, the phosphodiesterase PDE2A, is produced in large quantities in FXS mice. This enzyme breaks down cyclic AMP and cyclic GMP, important second messengers that are involved in brain development and function, particularly in memory and learning. When levels of PDE2A are too high, too much cyclic AMP is broken down and it can no longer perform its functions. To understand the involvement of PDE2A in FXS, Bardoni’s team administered the mice with an inhibitor of the enzyme and studied the effect of this treatment.

Long-term reduction in the effects of the disease

After administering the PDE2A inhibitor at 10, 14, and 21 days of life, the researchers observed an improvement in the abilities of the FXS mice to communicate, interact, and discriminate between individuals. “The treatment not only improved social communication problems in these mice, but also the morphology of their dendritic spines and synaptic plasticity in the regions of the brain studied, even after the end of the treatment. These results show that by intervening at a critical period of mice development, it is possible to reduce the effects of FXS over the long term,” said Bardoni.

What are the therapeutic prospects? Some drugs that target phosphodiesterases and are currently produced by the pharmaceutical industry could potentially be used to treat Fragile X syndrome. Bardoni’s team hopes to identify which of these drugs might act on PDE2A. This would make it possible to envisage new therapies for FXS being introduced very soon. The team also hopes to better identify the periods to be targeted by intervention in order to treat this syndrome, and to study the consequences of excess PDE2A in the brain at the molecular level. The researchers are also seeking to determine whether this therapeutic approach could be useful in other forms of social communication disorders and intellectual disability.

From the lab to the stage

Bardoni took part in the Binôme project: over a period of 50 minutes she met with playwright Sonia Rustic, and spoke to her about her research. Following their meeting, the dramatist created a half-hour play: Bobby and the Fragile X boy.“It was really exciting! I enjoyed this way of communicating with the general public, which is a particularly good way of engaging more people in relation to less common, less widespread illnesses, or illnesses that people don’t see as affecting them. The whole subject was handled in an intelligent and sensitive way,” reports the researcher.

For more on the Binôme project

Source: T. Maurin et al. Involvement of Phosphodiesterase 2A Activity in the Pathophysiology of Fragile X Syndrome. Cerebral Cortex, August 23, 2018. doi: 10.1093/cercor/bhy192.