Fragile X syndrome (FXS), a rare disease which is the most common inherited form of intellectual disability, is caused by an expansion in the FMR1 gene promoter which leads to silencing and loss of the FMRP protein (the "fragile X mental retardation protein").

Patients with FXS present varying degrees of intellectual disability, attention deficit disorder, anxiety, self-harming behaviour, autistic behaviour, macroorchidism, facial abnormalities and increased incidence of seizures. These symptoms occur in the population with this genetic mutation in a different ratio and in different ways between men and women, because the disease affects one in 4,000 males and one in 6,000-8,000 women.

Although there are treatments in an experimental phase for this disease, which use specific glutamate receptor subunits (mGluR5) and GABA receptors (GABA B) as their targets, the results obtained have not been very promising, and as such the disease has no specific treatment to date, and it is only possible to alleviate some of the symptoms.

A study published on 31 March in the online edition of the journal Nature Medicine, led by the team at the Neuropharmacology Laboratory - NeuroPhar at Pompeu Fabra University (Arnau Busquets-Garcia, Maria Gomis-González, Thomas Guegan, Rafael Maldonado and Andrés Ozaita), in UPF's Department of Experimental and Health Sciences shows that the endocannabinoid system is a new therapeutic target of great interest in the treatment of this disease.

Research groups at the CRG (Carmen Agustin-Pavon and Dierssen Mara), the IMIM (Antoni Pastor and Rafael de la Torre) and the University of the Basque Country (Susana Mato, Alberto Pérez-Samartín and Carlos Matute) also worked on the study.

New therapeutic target for treating fragile X syndrome

Using a murine model (tested in mice) which reproduces many of the symptoms of FXS in humans, the researchers showed that cannabinoid receptors play a key role in the disease's pathophysiology. Previous studies by the NeuroPhar research group reported that signalling through the endocannabinoid system is important in cognitive performance, feeling pain, anxiety and neuronal plasticity.

Using genetic and pharmacological approaches, the researchers observed that blocking the CB1 cannabinoid receptor normalizes cognitive deficits, the lack of sensibility to painful stimuli and susceptibility to epileptic seizures that appear in the FXS mouse model. These behavioural improvements were accompanied by biochemical changes in the mTOR intracellular signalling pathway, which is essential to cognitive processing, and the regularization of the density and maturity of neuronal dendritic spines. Furthermore, the pharmacological blocking of CB2 cannabinoid receptors normalized the phenotype of reduced anxiety presented by mice with this syndrome.

These results create an initial possible therapeutic approach for dealing with FXS by blocking the activity of the endocannabinoid system. The current lack of a treatment for this disease increases the interest in being able to validate the relevance of this new therapeutic strategy in the immediate future.

This research is the result of a collaborative project that began with funding from the Marató-TV3 Foundation (2009) for rare diseases, and has received funding from the Ministry for Competitiveness and Innovation, the ICREA Foundation and TECNIO.

Reference study: Busquets-Garcia A., Gomis-González M., Guegan T., Agustín-Pavón C., Pastor A., Mato S, Pérez-Samartín A., Matute C., de la Torre R., Dierssen M., Maldonado R., Ozaita A. " Targeting the endocannabinoid system in the treatme nt of fragile X syndrome". Nature Medicine doi: 10.1038/nm.3127. 31/3/2013.