Fragile X study offers hope for autism treatment

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The prospect of the first treatment for thousands of sufferers of a severe form of autism is raised by a study published today.

The research suggests that a certain class of drugs could help reverse Fragile X syndrome, the most common inherited cause of mild to severe intellectual disability and marked attention deficits, as well as social, language, emotional and behavioural problems.

These drugs are not yet approved, but are expected to go into human safety trials in America next year. If shown to be safe on adults, they will be tested on children, who are expected to benefit the most.

Hopes of the first treatment flow from a study, published today in the journal Neuron, in which mice developed to mimic the severe disease had diverse symptoms corrected by tinkering with a single gene.

"These findings have major therapeutic implications for Fragile X syndrome and autism," says lead author Prof Mark Bear, director of the Picower Institute for Learning and Memory at the Massachusetts Institute of Technology.

Autism is a catch-all term for a wide range of symptoms - usually marked by an inability to recognise and show emotions. Fragile X syndrome affects mostly boys at a rate of one in 4,000, with girls affected at half the rate and up to one-third of boys and young men with Fragile X qualify for having an autistic spectrum disorder.

Today's work backs the theory that many of the severe symptoms - learning disabilities, autistic behaviour, childhood epilepsy - stem from too much activation of a protein that picks up messenger chemicals in the brain - the metabotropic glutamate receptor, known as mGluR5.

"I think this may be relevant for children with mild autism too," Prof Bear told The Telegraph.

Fragile X and several other gene mutations that cause autism suggest that autistic behaviours may be linked to excessive manufacture of proteins in synapses, the junctions between brain cells. " If this hypothesis is correct, therapies targeting mGluR5 could be helpful," he says.

Fragile X is also marked by excessive and more spindly brain connections, memory loss, and changes to the growth and electrical properties of brain cells. "Remarkably, all these excesses can be reduced by reducing mGluR5," said Prof Bear.

Individuals with the syndrome have mutations in the FMR1 gene, which encodes the Fragile X mental retardation protein, FMRP.

The study found that FMRP and mGluR5 are at opposite ends of a kind of molecular seesaw. They keep each other in check, and without FMRP, the mGluR5 signals run rampant to cause the severe symptoms.

The research team found that a 50 per cent reduction in mGluR5, a realistic target in patients, fixed the many problems in the Fragile X mice, improving brain development and memory, restoring normal body growth, and reducing seizures.

The researchers used genetic engineering to reduce mGluR5, but the same thing could be accomplished by a drug. Although not yet approved by the US authorities, mGluR5 blockers are entering into human clinical trials.

"Insights gained by this study suggest novel therapeutic approaches, not only for Fragile X but also for autism and mental retardation of unknown origin," Prof Bear says.

"If the compounds are safe, the first efficacy trials would be in adults with Fragile X. maximum benefit is expected if the treatment is begun early in life, so ultimately the goal would be to have the drug approved for use in affected children.

Earlier this year, researchers led by Prof Susumu Tonegawa - the 1987 Nobel laureate and professor at MIT - used a different approach to fix Fragile X. By inhibiting an enzyme in the brain, the researchers managed to halt the development of the condition.

Lynne Zwink, of The Fragile X Society, said: "We welcome this breakthrough. Bringing up Fragile X children and caring for them in adulthood places enormous, life-long, strains on fragile X parents, who often have more than one child affected by fragile X in their family.

"There can be no better Christmas present for our families than they hear that scientists have taken Fragile X one step further along the road to a treatment."

The new findings, along with earlier work by Prof Adrian bird in Edinburgh on the most common cause of mental impairment seen in girls, provides strong evidence that brain damage can be reversed, even if the cause is present from the start of brain development.

The studies end an argument about whether - by the time a child is born - it is too late to counter the havoc caused by faulty genes.

The work of Prof Bird's team complements that of the Americans because it focused on a disorder at the extreme end of the spectrum of symptoms of autism, called Rett syndrome, which affects at least 10,000 children in the UK alone, mostly girls. The team found that it could make Rett symptoms disappear in mice by activating a specific gene.