By cutting in half the activity of a gene, scientists corrected many symptoms of a genetic defect in mice analogous to fragile X syndrome, a leading cause of inherited mental retardation in people.
The research suggests a new target for drug therapy for the condition, which is currently untreatable. However, it remains uncertain whether such drugs would benefit adults who have the disease. And it would take years of clinical trials to show whether drugs could check the disease’s progress in infants with the genetic defect.
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“I don’t think we’d be able to retrospectively correct the derailment of neural development that has occurred over decades” in adults, says lead scientist Mark Bear of the Massachusetts Institute of Technology. However, adults with the disease also suffer from abnormal signaling between nerves. A drug that targets the gene Bear’s team studied, which makes a protein called metabotropic glutamate receptor 5 (mGluR5), might be able to restore some mental functioning by improving this signaling, he says.
Research on mGluR5 “does show that a pharmacological therapy could work, that this receptor is a good target,” Bear says. A company that Bear cofounded, Seaside Therapeutics of Cambridge, Mass., is planning to start human-safety trials next year for a drug that reduces mGluR5 activity.
Mutations in a gene called fragile X mental retardation 1 (FMR1) cause the syndrome. The gene lies on the X chromosome, so girls can carry the mutation on one of their two X chromosomes without harm. Boys, who have only one X chromosome, develop symptoms about 3 years after birth if they have the mutation.
Normally, FMR1 throttles down protein production in the brain’s nerve cells, so people without a functioning FMR1 gene produce excess protein. According to one theory, the toxic buildup of protein leads to the symptoms of fragile X.
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Because mGluR5 accelerates protein synthesis in the brain, tempering mGluR5 activity could offset the effects of the FMR1 mutation and restore protein production to normal levels.
That’s exactly what Bear’s team found when they created a strain of mice that had the mutated fragile X gene and in which mGluR5 production was cut in half. Protein synthesis in the animals’ brains was normal, as were the nerves themselves, which normally have an excess of spiny structures in mice and in people with the mutated gene. Several other symptoms of the disease were also absent, including fast body growth, seizures, and memory problems, the team reports in the Dec. 20 Neuron.
However, the mice with reduced mGluR5 activity still had oversized testicles, a typical trait of fragile X.
“[The study] is very well done,” comments Stephen Warren of Emory University in Atlanta who has done related research on fragile X syndrome. “It’s not entirely clear whether a drug would be a cure,” Warren says, but he notes that a drug that targets mGluR5 might offer some benefit for patients, especially if treatment were started early in childhood.