A possible long-term treatment for Fragile X Syndrome

Researchers have found a possible treatment for Fragile X syndrome - the most common genetic cause of mental retardation in boys and the main single-gene cause of autism.

Fragile X syndrome is caused by a mutation on the X chromosome, in the Fragile x mental retardation 1 or FMR1 gene. It stops the protein that this gene codes for from being made. The protein, FMRP, is essential for brain development and for female fertility. Individuals with the mutation show symptoms including learning difficulties, problems with social interaction and physical symptoms like prominent ears and enlarged testicles in boys after puberty.

At the moment there isn't a treatment for the syndrome as a whole, and individual symptoms like hyperactivity and anxiety are treated separately. But now work carried out by Aubin Michalon and Michael Sidarov and their colleagues, published this week in the journal Neuron, has pointed to a possible treatment for multiple symptoms of Fragile X.

Previous work has shown that one of the ways FXS affects the brain is through one of the receptors for the neurotransmitter glutamate. This mGlu5 receptor behaves abnormally in patients with FXS and prevents proper signalling at the synapses between nerves in the brain, causing the cognitive impairment. Drugs that cause short term inhibition of these receptors have been shown to produce a reduction of symptoms, but until now, no studies of longer-acting mGlu5 inhibitors had been carried out.

Michalon and Sidarov worked with mice without the Fmr1 gene, that show similar learning and memory defecits to humans with FXS, as well as sharing a hypersensitivity to auditory stimuli. The team administered the drug CTEP to adolescent mice and then observed them after 4 weeks of treatment and 17 weeks of treatment. The idea of using adolescent mice and not newborns was to see if treatment with this drug could reverse symptoms in a brain that was almost fully developed, rather than preventing symptoms from developing in a still-developing brain.

After 4 weeks the treatment had reversed the deficit in learning and memory, and their hypersensitivity to sounds. And after 17 weeks, the mice showed a reduction in their hyperactivity and it also partially corrected their enlarged testicles, without causing any reduction in testosterone levels or general fitness of the mice.

mGlu5 inhibitors are already in clinical trials for Fragile X syndrome, so the researchers hope that they will show the breadth of improvements for patients as they found in their mouse study.