Researchers identify drug target for behavioral symptoms of fragile X syndrome

A drug currently undergoing testing as a treatment for cancer may also be effective against some symptoms of fragile X syndrome – an inherited form of autism. This is according to a study published in the journal Cell Reports.

The fragile X chromosome
Fragile X syndrome is caused by a mutation in the FMR1 gene located on the X chromosome.
Image credit: McGill University/University of Edinburgh

Fragile X syndrome, also known as Martin-Bell syndrome, is estimated to affect 1 in 4,000 males and 1 in 8,000 females in the US.

It is the most common genetic cause of autism, triggered by a mutation in a gene called FMR1 located on the X chromosome. This gene is responsible for making fragile X mental retardation 1 protein, or FMRP, which plays a part in the development of synapses in the brain.

A mutation in the FMR1 gene can prevent or impair the production of FMRP, which interferes with synaptic development. This can cause an array of developmental problems, including learning disabilities, behavioral problems and cognitive impairment.

There is currently no cure for fragile X syndrome, but the team involved in this latest research – from the University of Edinburgh in the UK and McGill University in Canada – found that an antifungal drug called cercosporamide, which is currently being tested as a drug candidate for cancer, improved behavior in mice with the disorder.

Cercosporamide blocks eIF4E activity, halting excess protein production in mice

Through their research, the team discovered that a molecule called eIF4E triggers excess production of a protein called MMP-9 in the brains of patients with fragile X syndrome.

Study co-author Nahum Sonenburg, of the Faculty of Medicine and the Goodman Cancer Research Centre at McGill University, explains that excess MMP-9 protein breaks down and rearranges synapses in the brain. “Excess MMP-9 disrupts communication between brain cells, leading to changes in behavior,” he adds.

On testing cercosporamide on mice with a form of fragile X syndrome, however, they found that the drug blocked the activity of eIF4E, which lowered the production of MMP-9. The team says this reversed behavioral symptoms of fragile X syndrome in the mice.

Co-first author Arkady Khoutorsky, a post-doctoral student at McGill University, says that although past studies have demonstrated that MMP-9 is involved in fragile X syndrome, theirs shows that its production can be controlled by blocking eIF4E activity with drugs that already exist.

Co-author Christos Gkogkas, of the Patrick Wild Centre for Research into Autism, Fragile X Syndrome and Intellectual Disabilities at the University of Edinburgh, adds:

“Our findings open the door to targeted treatments for fragile X syndrome. By designing treatments that block just this pathway, it is hoped that we can limit the potential side effects and develop therapies that are more efficient than general treatment approaches.”

A recent study led by researchers from Belgium, Italy and the Netherlands claims to provide better insight into the link between fragile X syndrome and autism.

The team found that FMRP regulates the maturation and positioning of cells in the brain’s cortex throughout embryonic development. The cortex is the brain region where information from other areas of the body is received, processed and interpreted; therefore impairments in FMRP – found in patients with fragile X syndrome – may lead to autism-related symptoms.