Fragile X Syndrome Corrected in Mice
WEDNESDAY Dec. 19, 2007 -- By targeting one gene, scientists have been able to correct many of the abnormalities associated with fragile X syndrome, the most common inherited form of childhood retardation.
Fragile X syndrome is caused by loss of the gene for "fragile X mental retardation protein" (FMRP). It affects about 100,000 people in the United States and is also a leading known genetic cause of autism.
There is currently no treatment or therapy for fragile X syndrome. Symptoms include mental retardation, epilepsy, and abnormal body growth.
"Fragile X is caused by the silencing of a single gene encoding FMRP," said lead researcher Mark F. Bear, director of the Picower Institute and the Picower professor of neuroscience at MIT in Cambridge, Mass. "FMRP regulates protein synthesis in the brain," he explained.
But the findings suggest that a drug could correct many of the symptoms of the disease.
"You are not doomed with the absence of this gene," Bear said. "If we could even come in late and correct it, there is a good chance that we could alter brain development and improve the symptoms," Bear said.
The report is published in the Dec. 20 issue of Neuron.
In the study, Bear's team used mice engineered to lack the FMRP gene. This caused the animals to develop many of the characteristics of human fragile X syndrome.
The lack of FMRP acts as a brake on protein synthesis in specific areas of brain circuitry. According to Bear's group, loss of this genetic "brake" allows another protein driving the syndrome -- called metabotropic glutamate receptor 5 (mGluR5) -- to get out of control.
So, a lack of functioning FMRP brings about runaway protein synthesis, Bear noted. But, "if we could dial back activity at the mGluR5 receptor, we might be able to bring the system back into balance and correct fragile X syndrome," he theorized.
Investigating that notion, Bear's team created mutant mice that lacked both the FMRP gene and had a 50 percent reduction in their production of mGluR5. They reduced rather than eliminated the activity of mGluR5, so that they could mimic what might happen if a drug treatment for fragile X was used in humans.
The mouse tests showed that the reduction in the mGluR5 gene could stop many of the abnormalities caused by the absence of FMRP. The double-mutant mice showed an improvement in their brain structure and function, in their brains' ability to make key proteins, as well as in memory and body growth.
Animals without the FMRP gene did produce an overgrowth of the spinal neurons called dendritic spines. However, the accompanying 50 percent reduction in mGluR5 allowed mice to maintain normal spine density.
In addition, the double mutant mice had substantial reductions in epileptic seizures, the researchers found.
Based on these results, human trials focused on mGluR5 should begin next year, Bear said. "I am cautiously optimistic that we will be able to correct some of the symptoms of the disease," he said.
One expert believes that mGluR5 could be a powerful target for correcting fragile X syndrome.
"This is a very important paper that demonstrates a remarkable rescue of fragile X features when the knockout mouse is crossed with a mGluR5-deficient mouse," said Dr. Randi Hagerman, a professor of pediatrics and medical director of the M.I.N.D. Institute at the University of California, Davis.
This is "wonderful" support for the therapeutic use of drugs known as mGluR5 antagonists in the treatment of fragile X syndrome, Hagerman said.
"Although there was good evidence for this treatment in the trial of mGluR5 antagonists in the knockout mouse [lacking FMRP] and other animal models of fragile X, this genetic evidence further supports treatment trials and suggests that earlier use of these agents may be very beneficial, since the genetic model corrects this problem throughout development," Hagerman said.
"We are initiating mGluR5 antagonist trials in humans now, and we are excited to see the benefit in adults with fragile X," Hagerman said. "This work is ushering in a new age of targeted treatments for fragile X syndrome."
Another expert agreed.
"Needless to say, we are very excited about this publication, which has actually been in the works for a long time," said Dr. Michael Tranfaglia, the medical director of the FRAXA Research Foundation, which is focused on fragile X. "The genetic rescue of most of the major features of fragile X syndrome by decreasing the expression of mGluR5 is an elegant and powerful demonstration of the 'mGluR5' theory.'"
In this case, the breakthrough finding has led to the conclusion that fragile X syndrome is primarily the result of excessive activity in a single cellular receptor pathway, Tranfaglia said.
Drugs are currently in development that can block this receptor, Tranfaglia said. "We believe these drugs have enormous potential for the treatment of fragile X and related developmental disorders, including many cases of autism," he said.
For more about fragile X syndrome, visit the Fragile X Research Foundation.
Posted: December 2007