Because neurons are postmitotic—unable to divide or regenerate once formed in the brain—scientists long believed that neurodevelopmental diseases were irreversible. Recent research began to challenge that thinking, and a mouse study in yesterday’s Neuron offers compelling evidence that Fragile X syndrome (FXS)—the most common inherited form of mental retardation—can be reversed well after symptoms have developed. A team led by Lothar Lindemann of Hoffman-La Roche in Basel, Switzerland, and Mark Bear of the Massachusetts Institute of Technology fixed a wide array of defects in adult FXS mice using a compound that blocks the mGlu5 form of metabotropic glutamate receptor. The findings lend hope for mGlu5 agents being tested in ongoing clinical trials of people with Fragile X and related brain disorders.

Afflicting one in 4,000 boys and about half as many girls, Fragile X syndrome arises from disruptions in a single X-chromosome gene, Fmr1, reducing expression of Fragile X mental retardation protein (FMRP). “Excess” characterizes many Fragile X features—among them excessive excitability, body growth, and synaptic connectivity. Many FXS symptoms have been linked to overactive mGlu5 receptors, which drive synthesis of synaptic proteins. That led Bear to propose that FMRP acts to suppress mGlu5-triggered protein synthesis. According to his theory, mGlu5 activity goes unfettered without FMRP, producing the diverse problems seen in Fragile X (Bear et al., 2004). A genetic study by Bear and colleagues supported this idea—Fmr1 knockout (KO) mice with only one copy of the Grm5 gene and half normal mGlu5 activity were spared a slew of abnormalities seen Fmr1 KO controls (ARF related news story on Dölen et al., 2007). While that work established proof of principle that dampening mGlu5 could prevent FX deficits, it did not show that they could be reversed later in life. Other groups improved symptoms in adult mouse and fly Fragile X models using a mGlu5 antagonist (MPEP) (Yan et al., 2005; ARF related news story on McBride et al., 2005), but it was only partial relief, and some animals developed tolerance to the compound. The current paper shows “we can intervene pharmacologically after symptom onset and correct many aspects of Fragile X,” Bear told ARF.

Led by co-first authors Aubin Michalon of Roche and Michael Sidorov of MIT, the researchers treated Fmr1 knockout mice with a different mGlu5 blocker, a pyridine derivative called CTEP (Lindemann et al., 2011). Though discovered at Roche, CTEP is not being developed by the company as a human drug, but “has ideal properties for studies in rodents,” Lindemann said. The compound not only has great pharmacokinetics and oral bioavailability, but also is considerably more potent and long-lasting than commercially available mGlu5 inhibitors, for example, MPEP and another Roche compound, fenobam (Porter et al., 2005). In mouse studies, those molecules need to be given four to five times a day because their half-life is a mere hour or two. By comparison, CTEP acts for about 18 hours, allowing researchers to see some symptoms improve in Fmr1 knockout mice after just a single subcutaneous dose (2 mg/kg body weight). For chronic dosing experiments, the mice were given this amount of the inhibitor every other day for four to 17 weeks.

With the exception of macroorchidism (medical speak for enlarged testes), which was only partially rescued, all nine phenotypes analyzed in the study returned to normal with CTEP treatment. Fmr1-deficient mice become startled easily and have trouble acclimating to their environment. They also have problems remembering where danger signals (e.g., foot shocks) are. CTEP rescued these behavioral deficits. Fmr1 knockout mice respond to loud noise with seizures, and have exaggerated hippocampal long-term depression. These, too, were fully corrected by the compound. Moreover, CTEP restored the elevated spine density and protein synthesis rates to normal, and abolished hyperactive ERK kinase and mTOR signaling typically seen in Fmr1 knockouts.

“This article demonstrates that the kind of therapeutic intervention we can realistically implement in patients is extraordinarily effective in reversing the major Fragile X phenotypes at cellular, synaptic, neural circuit, and behavioral levels,” noted Michael Tranfaglia of FRAXA Research Foundation, which funds Fragile X research (see full comment below).

Before the current paper came out, Roche and several other companies had begun developing mGlu5 inhibitors for Fragile X. Roche completed a six-week Phase 2 trial of its compound, R04917523, but results have not been reported. “I am unfortunately unable to disclose data,” Lindemann noted. “We can say, though, that the data obtained so far support continuation of the clinical development of the molecule.” A larger, 12-week Phase 2 study is in the works, with recruitment to begin “any day,” Lindemann said.

Seaside Therapeutics, Inc., of Cambridge, Massachusetts, a company Bear co-founded in 2005, has several Fragile X compounds in its clinical pipeline. One of them—a mGluR antagonist (STX107) licensed from Merck—survived Phase 1 but has languished on the backburner while the company pours resources into another compound—a GABA B receptor agonist (STX209). By ramping up inhibitory activity, this molecule achieves the same effect as mGlu5 blockers—diminished glutamate receptor signaling—but has a faster path to regulatory approval, Bear told ARF. It is the active enantiomer of a drug (racemic baclofen) already in use for cerebral palsy and gastroesophageal reflux. The company reported at meetings that the GABA B agonist improved several global measures in an open-label Phase 2 study of autistic patients (see news release). In the Fragile X Phase 2 trial, the compound showed some benefit in participants with severe social avoidance (see news release). Recruitment is underway for a Phase 3 trial of the GABA B agonist in children with Fragile X syndrome.

But the frontrunner may be Novartis’ AFQ056, which has headed into Phase 3 testing. In a Phase 2 trial of 30 men with FXS, the mGlu5 blocker seemed to help a subset of participants with strong Fmr1 gene silencing (Jacquemont et al., 2011).

Might the present findings apply to neurodegenerative disease? Conceptually, it may be hard to see a connection, because in Alzheimer’s and Parkinson’s, for example, neurodegeneration occurs in discrete brain regions, whereas Fragile X deficits are widespread and primarily synaptic, noted Gül Dölen, now at Stanford University, California, but who obtained her Ph.D. under Bear. Still, there is some evidence that these disparate disorders could share molecular underpinnings. APP translation appears to be regulated by Fmr1 through mGlu receptors (see Westmark and Malter, 2007 and ARF Webinar), and people with Fragile X have unusually high brain Aβ levels (see Malter et al., 2010). On the clinical front, Novartis’ mGlu5 antagonist looked promising for PD patients who have developed dyskinesias as a side effect of dopamine-boosting drugs (Berg et al., 2011). Excess glutamate has been blamed for these disabling motor problems, and a drug (amantadine) that blocks glutamate signaling through AMPA receptors is currently used to treat PD patients with dyskinesias.—Esther Landhuis


  1. This work is an impressive confirmation of the metabotropic glutamate receptor (mGluR) theory of Fragile X syndrome, and it extends our understanding of the therapeutic mechanisms of this important new drug class. This is the first report of chronic treatment of this duration, made possible by this new agent (CTEP), which is significantly more potent and much longer acting than any other available research agent. Other studies have shown excellent preclinical efficacy later in (mouse) life, and studies of conditional knockout mice also strongly suggest that most symptoms of Fragile X are potentially reversible, but this article demonstrates that the kind of therapeutic intervention that we can realistically implement in patients is extraordinarily effective in reversing the major Fragile X phenotypes at all levels (cellular, synaptic, neural circuit, and whole animal/behavioral).

    One of the past critiques of the mGluR5 antagonist treatment strategy for Fragile X was that some animal studies showed development of tolerance over the course of a few days of chronic treatment. One paper on which I was a coauthor (Yan et al., 2005) showed some tolerance, though we did not believe this was necessarily a predictor of human tolerance. No tolerance was seen with this long-term, high-level mGluR5 antagonism by CTEP, which bodes quite well for human clinical trials currently underway. CTEP also appears to be quite similar pharmacokinetically to the Roche drug currently under development for Fragile X, and this study appears to justify the use of long-half-life drugs that achieve steady antagonism of mGluR5. It is also remarkable that high-level antagonism of mGluR5 (well over 50 percent) results in no apparent adverse effects, in line with clinical observation of excellent tolerability of these drugs in patients. This is a powerful research tool, since far fewer administrations of drug are required in animal models—frequent administration of drugs results in powerful stress-related confounds in this type of chronic dosing study, and that was clearly absent here. CTEP will likely be in great demand for this use. Frequent drug administration and fluctuating drug levels are also problematic in clinical therapeutics as well, so this type of drug may be superior for many reasons, not least of which are adherence and efficacy.

    There may be a great many potential uses for mGluR5 antagonists for a wide range of neuropsychiatric conditions. Clinical trials of this class in L-dopa-induced dyskinesia of Parkinson's disease (PD-LID) have been uniquely successful; this alone should justify marketing. This class also has great promise for the treatment of a broad range of addictions, and long-acting agents such as this would be ideal for this application. Of course, we are most intrigued by the potential of mGluR5 antagonists for treating other forms of autism spectrum disorders; it appears likely that some (though not all) cases of non-fragile-X-autism involve similar abnormalities in these same signaling pathways. Biomarkers such as APP may reveal individuals without the Fragile X mutation who also have hyperactive signaling similar to Fragile X (APP translation is known to be regulated by FMRP via mGluR, as Cara Westmark has shown (see ARF Webinar); Sokol et al. have shown elevated APP levels in a subset of autism patients—usually more severely affected individuals (Sokol et al., 2006). These individuals may be potential responders to this type of treatment. It is also possible that mGluR5 antagonists could be an effective component of a cocktail treatment for Alzheimer's disease, for example, by decreasing translation of APP while co-administration of a secretase inhibitor could reduce abnormal metabolism.

    Intriguingly, Fatemi et al. recently published several postmortem studies suggesting that low levels of FMRP are associated with many different neuropsychiatric disorders—not just autism, but also Alzheimer's, schizophrenia, bipolar disorder, and other mood disorders (Fatemi et al., 2010). Decreased FMRP levels, from whatever primary cause, could lead to excessive signaling in these same pathways, and mGluR5 antagonists could be useful treatments in these cases. FMRP itself could end up as an important biomarker, even in cases other than developmental disorders


    . Suppression of two major Fragile X Syndrome mouse model phenotypes by the mGluR5 antagonist MPEP. Neuropharmacology. 2005 Dec;49(7):1053-66. PubMed.

    . High levels of Alzheimer beta-amyloid precursor protein (APP) in children with severely autistic behavior and aggression. J Child Neurol. 2006 Jun;21(6):444-9. PubMed.

    . Fragile X mental retardation protein levels are decreased in major psychiatric disorders. Schizophr Res. 2010 Dec;124(1-3):246-7. PubMed.

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News Citations

  1. Halving Glutamate Receptors Restores Balance in Fragile X Mouse
  2. Tamping Down Glutamate Receptors Cures Synapses in Fly Retardation Model

Webinar Citations

  1. Alzheimer Disease—The Fragile X Syndrome Connection

Paper Citations

  1. . The mGluR theory of fragile X mental retardation. Trends Neurosci. 2004 Jul;27(7):370-7. PubMed.
  2. . Correction of fragile X syndrome in mice. Neuron. 2007 Dec 20;56(6):955-62. PubMed.
  3. . Suppression of two major Fragile X Syndrome mouse model phenotypes by the mGluR5 antagonist MPEP. Neuropharmacology. 2005 Dec;49(7):1053-66. PubMed.
  4. . Pharmacological rescue of synaptic plasticity, courtship behavior, and mushroom body defects in a Drosophila model of fragile X syndrome. Neuron. 2005 Mar 3;45(5):753-64. PubMed.
  5. . CTEP: a novel, potent, long-acting, and orally bioavailable metabotropic glutamate receptor 5 inhibitor. J Pharmacol Exp Ther. 2011 Nov;339(2):474-86. PubMed.
  6. . Fenobam: a clinically validated nonbenzodiazepine anxiolytic is a potent, selective, and noncompetitive mGlu5 receptor antagonist with inverse agonist activity. J Pharmacol Exp Ther. 2005 Nov;315(2):711-21. PubMed.
  7. . Epigenetic modification of the FMR1 gene in fragile X syndrome is associated with differential response to the mGluR5 antagonist AFQ056. Sci Transl Med. 2011 Jan 5;3(64):64ra1. PubMed.
  8. . FMRP mediates mGluR5-dependent translation of amyloid precursor protein. PLoS Biol. 2007 Mar;5(3):e52. PubMed.
  9. . Fragile X Syndrome and Alzheimer's Disease: Another story about APP and beta-amyloid. Curr Alzheimer Res. 2010 May;7(3):200-6. PubMed.
  10. . AFQ056 treatment of levodopa-induced dyskinesias: results of 2 randomized controlled trials. Mov Disord. 2011 Jun;26(7):1243-50. PubMed.

External Citations

  1. six-week Phase 2 trial
  2. 12-week Phase 2 study
  3. news release
  4. news release
  5. Phase 3 trial
  6. Phase 3 testing

Further Reading


  1. . Correction of fragile X syndrome in mice. Neuron. 2007 Dec 20;56(6):955-62. PubMed.
  2. . CTEP: a novel, potent, long-acting, and orally bioavailable metabotropic glutamate receptor 5 inhibitor. J Pharmacol Exp Ther. 2011 Nov;339(2):474-86. PubMed.
  3. . Fragile X syndrome and targeted treatment trials. Results Probl Cell Differ. 2012;54:297-335. PubMed.
  4. . Targeted treatments for fragile X syndrome. J Neurodev Disord. 2011 Sep;3(3):193-210. PubMed.
  5. . Pharmacological rescue of synaptic plasticity, courtship behavior, and mushroom body defects in a Drosophila model of fragile X syndrome. Neuron. 2005 Mar 3;45(5):753-64. PubMed.

Primary Papers

  1. . Chronic pharmacological mGlu5 inhibition corrects fragile X in adult mice. Neuron. 2012 Apr 12;74(1):49-56. PubMed.