|
Researchers Reverse Key Symptoms of Fragile X in Mice In the December 20thissue of Neuron, MIT researchers Mark Bear, Gul Dolen, and others, along with Sumantra Chattarji of India’s National Center for Biological Sciences, show that they can correct major symptoms of Fragile X by reducing expression of a single receptor in the brain. This receptor, a protein called mGluR5, is a prime target for drugs to treat Fragile X – and possibly autism – in humans.The findings support the theory that key Fragile X symptoms – learning disabilities, autistic behavior, and seizures – stem from too much activation of one of the brain’s chief network managers – the metabotropic glutamate receptor mGluR5. People with Fragile X lack a protein called FMRP(Fragile X Mental Retardation Protein). This 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, mGluR5 signals run rampant. To test this theory, the researchers knocked out one of the two copies of the mGluR5 gene in mice already lacking FMRP. The mice lacking FMRP showed many of the symptoms observed in humans who have Fragile X. By knocking out one copy of mGluR5, the researchers created mice that produced only half the normal amount of mGluR5 protein, hoping to compensate for the lack of FMRP and eliminate symptoms of Fragile X.”We decided to reduce the mGluR5 levels by 50 percent to reflect what might be a therapeutically relevant condition that would be achievable with carefully titrated drug treatment,” said Bear. “Total knockout of mGluR5 has deleterious effects, whereas reducing it by half is innocuous.”The researchers found that reducing mGluR5 eliminated many symptoms of the disorder. Like humans with Fragile X, mice without FMRP experience seizures, impaired memory, and accelerated body growth. When mGluR5 was diminished, these problems were corrected.Reducing mGluR5 also compensated for changes in the brain associated with increased protein synthesis. With less mGluR5, the brain of each mouse no longer formed an excessive number of neuronalconnections. The mice did not have the high density of dendritic spines that is characteristic of Fragile X syndrome. Furthermore, the total rate of protein synthesis was reduced to normal levels in the brains of Fragile X mice with reduced mGluR5.The researchers used genetic engineering to reduce mGluR5, but the same thing could be accomplished by a drug. Pharmaceutical companies have already developed experimental drugs that block mGluR5. Clinical trials are underway, but none of the drugs has yet been approved for humans.These findings may lead to further targets for drug discovery, since scientists can now study other drugs which affect other elements of the brain’s mGluR pathway. It should be possible to identify biomarkers, substances which can be measured in the blood, which can identify changes in the function of the mGluR pathway in people with developmental disorders. Through biomarkers, other people with autism and developmental disorders who do not have Fragile X, but do have abnormalities in this pathway, can be identified. It is likely that these individuals would respond to many of the treatments currently being developed for Fragile X.FRAXA has provided funding for the work of Mark Bear and colleagues every year since 2000 and also funds Sumantra Chattarji . FRAXA is now working with several companies to help speed development of mGluR5 blockers to treat Fragile X. Stay tuned for future announcements! |
