04-27-2006, 09:50 PM
Science 28 April 2006:
Vol. 312. no. 5773, p. 521
DOI: 10.1126/science.312.5773.521
BIOMEDICAL RESEARCH:
A Fix for Fragile X Syndrome?
Greg Miller
The cognitive and behavioral problems associated with Fragile X syndrome would seem to be irreversible, because they're caused by a genetic glitch that derails the development of the nervous system. Yet much to their surprise, some researchers say that many of these problems might be fixable with drugs. Within a year, they predict, clinical trials will be under way to test compounds that target a family of receptors believed to play a critical role in symptoms of the inherited disorder. "I've been working on Fragile X for 25 years, and I never thought I'd be working on a drug," says Stephen Warren, a geneticist at Emory University in Atlanta, Georgia.
The drugs Warren and others envision would target the so-called metabotropic glutamate receptor (mGluR) that sits on the surface of neurons. The idea that mGluRs might be important actors in Fragile X arose from a chance meeting several years ago between Warren and Mark Bear, a neuroscientist now at the Massachusetts Institute of Technology in Cambridge.
At a gathering of Howard Hughes Medical Institute investigators, Bear had described recent work suggesting that mGluRs are crucial for weakening synaptic connections between neurons in the hippocampus, a brain region involved in learning and memory. Such weakening, called long-term depression (LTD), is an important form of neural plasticity during brain development and may underlie changes in neural connectivity that support learning later in life. Bear's lab had discovered that LTD requires activation of mGluRs in order to translate crucial mRNA molecules floating near synapses into proteins.
Warren, who'd been studying FMRP, the protein that's missing in Fragile X, happened to sit next to Bear after the mGluR talk and introduced himself. Warren's team had found that FMRP suppresses the kind of protein synthesis that Bear had discovered to be essential for LTD. "We began an animated conversation," Bear says. By the end of it, Warren had agreed to send Bear some Fragile X mice, which have a mutation that mimics that in people with the syndrome.
Warren, Bear, and colleagues reported in 2002 that these mice have enhanced LTD compared to normal mice. This propensity to weaken synapses could slow brain maturation and contribute to the developmental and cognitive problems seen in people with Fragile X, Bear and Warren later argued in an article published in 2004 in Trends in Neuroscience. Based on this and other evidence, the authors proposed that drugs that block mGluRs could mitigate many symptoms of Fragile X by performing the job normally done by FMRP: putting a check on mGluR-mediated protein synthesis.
Tests with such compounds in fly and mouse models of Fragile X have lent support for that suggestion. Flies missing the gene that encodes FMRP have altered courtship behavior, impaired learning and memory, and altered anatomy in a brain structure involved in learning--all of which can be reversed with a compound that blocks mGluRs, a team led by Thomas Jongens at the University of Pennsylvania reported in the 3 March 2005 issue of Neuron.
Blockers of mGluRs also reverse impairments in Fragile X mice, at least in some experiments, says Ben Oostra of Erasmus University in Rotterdam, the Netherlands. Oostra suspects, however, that mGluR blockers won't alleviate all Fragile X symptoms. "I am optimistic that some defects like epilepsy and autistic behavior and maybe hyperactivity might benefit, but I am more pessimistic about other parts of the phenotype of Fragile X," he says.
Bear and Warren have each started a company to investigate candidate drugs. Bear is testing mGluR blockers under license from Merck in animals, whereas Warren is screening compounds that may interfere with related cell signaling pathways. "We're doing animal toxicity studies now to ensure they're safe," says Bear. "So far they look very safe." He hopes to soon secure permission for a clinical trial.
Vol. 312. no. 5773, p. 521
DOI: 10.1126/science.312.5773.521
BIOMEDICAL RESEARCH:
A Fix for Fragile X Syndrome?
Greg Miller
The cognitive and behavioral problems associated with Fragile X syndrome would seem to be irreversible, because they're caused by a genetic glitch that derails the development of the nervous system. Yet much to their surprise, some researchers say that many of these problems might be fixable with drugs. Within a year, they predict, clinical trials will be under way to test compounds that target a family of receptors believed to play a critical role in symptoms of the inherited disorder. "I've been working on Fragile X for 25 years, and I never thought I'd be working on a drug," says Stephen Warren, a geneticist at Emory University in Atlanta, Georgia.
The drugs Warren and others envision would target the so-called metabotropic glutamate receptor (mGluR) that sits on the surface of neurons. The idea that mGluRs might be important actors in Fragile X arose from a chance meeting several years ago between Warren and Mark Bear, a neuroscientist now at the Massachusetts Institute of Technology in Cambridge.
At a gathering of Howard Hughes Medical Institute investigators, Bear had described recent work suggesting that mGluRs are crucial for weakening synaptic connections between neurons in the hippocampus, a brain region involved in learning and memory. Such weakening, called long-term depression (LTD), is an important form of neural plasticity during brain development and may underlie changes in neural connectivity that support learning later in life. Bear's lab had discovered that LTD requires activation of mGluRs in order to translate crucial mRNA molecules floating near synapses into proteins.
Warren, who'd been studying FMRP, the protein that's missing in Fragile X, happened to sit next to Bear after the mGluR talk and introduced himself. Warren's team had found that FMRP suppresses the kind of protein synthesis that Bear had discovered to be essential for LTD. "We began an animated conversation," Bear says. By the end of it, Warren had agreed to send Bear some Fragile X mice, which have a mutation that mimics that in people with the syndrome.
Warren, Bear, and colleagues reported in 2002 that these mice have enhanced LTD compared to normal mice. This propensity to weaken synapses could slow brain maturation and contribute to the developmental and cognitive problems seen in people with Fragile X, Bear and Warren later argued in an article published in 2004 in Trends in Neuroscience. Based on this and other evidence, the authors proposed that drugs that block mGluRs could mitigate many symptoms of Fragile X by performing the job normally done by FMRP: putting a check on mGluR-mediated protein synthesis.
Tests with such compounds in fly and mouse models of Fragile X have lent support for that suggestion. Flies missing the gene that encodes FMRP have altered courtship behavior, impaired learning and memory, and altered anatomy in a brain structure involved in learning--all of which can be reversed with a compound that blocks mGluRs, a team led by Thomas Jongens at the University of Pennsylvania reported in the 3 March 2005 issue of Neuron.
Blockers of mGluRs also reverse impairments in Fragile X mice, at least in some experiments, says Ben Oostra of Erasmus University in Rotterdam, the Netherlands. Oostra suspects, however, that mGluR blockers won't alleviate all Fragile X symptoms. "I am optimistic that some defects like epilepsy and autistic behavior and maybe hyperactivity might benefit, but I am more pessimistic about other parts of the phenotype of Fragile X," he says.
Bear and Warren have each started a company to investigate candidate drugs. Bear is testing mGluR blockers under license from Merck in animals, whereas Warren is screening compounds that may interfere with related cell signaling pathways. "We're doing animal toxicity studies now to ensure they're safe," says Bear. "So far they look very safe." He hopes to soon secure permission for a clinical trial.