Fragile X fixed in mice
Animal studies suggest a way to treat the devastating mental retardation disorder.
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.
The findings, published today in Neuron1, 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.
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 had suggested that overproduction of mGluR5 could be responsible for fragile X defects.
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.
Other researchers praised the study. “People have had a hell of a time getting behavioural phenotypes from fragile-X mice," says Justin Fallon, who researches fragile X at Brown University in Providence, Rhode Island. "This has been a stumbling block for the field."
Scientists have been hoping for advances for some time. 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 activation3. The current study, by using genetics to correct the defects, provides a clear indication that mGluR5 is the right target.
"This is a directly translatable result," says Bear, who has founded a company, Seaside Therapeutics in Cambridge, Massachusetts, that is focused on bringing glutamate-blocking drugs to clinical trials. He also says he sees potential for treating some forms of autism. Only a small percentage of people with autism have the fragile-X mutation, but many people with fragile X satisfy the diagnostic criteria for autism. “I’d be extremely pleased if all we accomplished was correcting fragile X in humans," says Bear. "But we think and it’s possible that this work on fragile X could extend into autism in general.”
Still, challenges remain. Bear says that Seaside Therapeutics has applied to the US Food and Drug Administration to test a compound, one of several mGluR antagonists licenced 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.
Still, Bear is hopeful that the major obstacles have been overcome. “We have a lot of question marks that still face us," he says. "I think that at the very least we’ve established a great target.”
- Dölen, G. et al. Neuron 56, 955-962 (2007).
- Huber, K. M., Gallagher, S. M., Warren, S. T. & Bear, M. F. Proc. Natl Acad. Sci. USA 99, 7746-7750 (2002).
- McBride, S. M. et al. Neuron 45, 753-764 (2005).