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Sci Tech
Fragile X fixed in mice
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Almost all symptoms reversed in mouse model Genetics was used to home in on target
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Researchers have reversed almost all symptoms of fragile-X syndrome in a mouse model for the disease. In humans, fragile X is the most common form of heritable mental retardation and one of the leading known causes of autism.
Exciting find
The findings add to evidence suggesting a cause of fragile X defects — with possible therapeutic implications.
“I think it’s an exciting set of findings that indicates a clear route to attempt treatment for a significant set of fragile-X symptoms,” says Thomas Jongens, a neurogeneticist at the University of Pennsylvania School of Medicine in Philadelphia, who was not involved in the research.
Useful model
Male mice have only one copy of the gene that encodes the fragile-X mutant related protein FMRP, which is — as its name suggests — mutated in the disease. When this gene is knocked out, the males produce a useful, if imperfect, model for the human disease.
A team led by Mark Bear, director of the Picower Institute for Learning and Memory at the Massachusetts Institute of Technology in Cambridge, crossed these mice with other mice lacking a copy of a specific receptor protein called mGluR5.
Earlier work
Earlier work had suggested that overproduction of mGluR5 could be responsible for fragile Xdefects.
The offspring of these crossed mice did not suffer from symptoms, which can include seizures, altered neuronal physiology and a kind of exaggerated forgetfulness of some learned behaviour.
In 2002, Bear and his colleagues proposed that FMRP might put a brake on the activation of mGluR2. Over the years the theory has stood up to testing in models for the disease, including in fruit-fly studies by Jongens that showed the disease could be reversed in flies with drugs that block mGluR activation.
Clear indication
The current study, by using genetics to correct the defects, provides a clear indication that mGluR5 is the right target. Still, challenges remain.
Bear says that Seaside Therapeutics has applied to the U.S. Food and Drug Administration to test a compound, one of several mGluR antagonists licensed from Merck, in adult humans.
If approved, drug trials could start as early as next year — but this class of drugs has traditionally produced mixed results and no compounds are currently approved for any condition.
BRENDAN MAHER
Nature News Service
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