Fragile X, a “disorder of excess,” and a potential drug treatment

Back in June, scientists at the Picower Institute for Learning and Memory at the Massachusetts Institute of Technology (MIT) genetically manipulated mice to have Fragile X Syndrome: Then, by inhibiting a brain enzyme, p21-activated kinase, or PAK (which “affects the number, size and shape of connections between neurons and the brain”), the scientists found that the “brain abnormalities in the FXS mice were reversed.” These findings were reported in the June 25-29 issue of the Proceedings of the National Academy of Science.

Fragile X is the most common form of heritable mental retardation and the leading identifiable cause of autism (responsible for about 5% of cases of autism). Today, the journal Neuron reports on the correction of Fragile X syndrome in mice. Many of the symptoms of FXS are, the study notes, caused by the unchecked activation of mGluR5, a metabotropic glutamate receptor. Researchers bred special mice who had the FXS trait and also a 50% reduction in mGluR5 expression. The December 19th Time magazine quotes the lead researcher, Mark Bear: “‘ Fragile X is a disorder of excess……There are too many synapses, accelerated body growth, excessive protein synthesis, and excessive excitability, which leads to epilepsy.’”

Scientists have suspected that FRMP exerts its braking action by attaching to receptors on the surface of brain cells, known as mGR5 receptors (the G is for glutamate, a key signaling agent in the brain). They reasoned that it would be possible to correct the excesses of Fragile X by blocking these receptors, which act as accelerators of protein production. To test this idea, the researchers produced a special breed of mice that had the Fragile X trait but only half the normal number of mGR5 receptors. The result, explains Bear: “We were able to correct the excesses [of Fragile X], taking our foot off the accelerator.”

What was especially remarkable was the number of ways the intervention reversed Fragile X symptoms. The specially bred mice had fewer seizures, more normal brain structure, a more typical rate of body growth and they performed better on a learning task than mice with uncorrected Fragile X. The experiment suggests that treating Fragile X with a drug that inhibits mGR5 receptors could have similarly healing effects.

Time magazine also notes that Bear has founded a company, Seaside Therapeutics, that is hoping to start testing on STX 107, a drug that would be an effective mGR5 inhibitor. While it is hoped that such as drug might help children and adults with FXS, “early intervention in childhood would seem to offer the most promise.” Seaside Therapeutics also plans to test the drug on individuals with autism and “other disorders of brain development.”