Fragile X syndrome is the most common genetic causes of intellectual disability, affecting about 1 in 4,000 people with more males affected than females, and also the most common genetic cause of autism, being responsible for 2-6% of all cases of autism. While no drugs have yet been approved to treat Fragile X syndrome, there is considerable interest in the biomedical research community in this condition, since as well as being a significant cause of disability in its own right it is a condition whose study may well help medical science to develop effective therapies for other forms of autism.
Fragile X syndrome is caused by mutations that silence the Fragile X (FMR1) gene and lead to a reduction –or absence – of the fragile X mental retardation protein (FMRP) and by knocking out the corresponding Fmr1 gene in mice and other organisms scientists have been able to generate models for the evaluation of potential therapies for autistic spectrum disorders , such as the drug Arbaclofen whose development we discussed briefly in 2010.
While it was clear quite early on that FMRP plays an important role at the synapse – the structure that allows nerve signals to be passed from one neuron to another – the nature of that role was not obvious, though a series of experiments in a variety of animal models had indicated that a class of proteins known as the metabotropic glutamate receptors might be involved. A key discovery was made by Professor Mark Bear at MIT, who demonstrated that FMRP acted as a counterbalance to metabotropic glutamate receptor sub-type 5 (mGluR5). mGluR5 increases protein synthesis at the synapse as a means to facilitate signal transmission through the brain, and FMRP acts to reduce protein production. In the absence of FMRP signaling at the synapse goes awry, leading to the symptoms observed in fragile X syndrome. This key scientific breakthrough was made in 2007 by Prof. Bear by genetically engineering Fmr1 knockout mice to halve the production of mGluR5, resulting in a significant reduction in fragile X symptoms in these mice. This linking of alteration in the expression of the gene to changes in fragile X symptoms was an important result, indicating that it may be possible to treat Fragile X by reducing the amount or the activity of mGluR5.
However, using gene modification to knock-down mGluR5 activity in people with Fragile X syndrome is not a practical option at this time, so attention turned to identifying drugs that could block mGluR5. Last week in a paper in the journal Neuron Prof. Bear’s team, working in collaboration with scientists at the Swiss healthcare company Roche ,announced another major breakthrough. This study used an experimental mGluR5 inhibitor known as CTEP which had recently been shown in animal studies to be far more selective for mGlu5 than previous mGluR5, as well as having a longer half-life in vivo making it an ideal candidate for studies where mGLuR5 activity needed to be suppressed for extended continuous periods. They showed that CTEP treatment could not only stop the worsening of the condition but actually reversed the symptoms in FMR1 knockout mice with established Fragile X syndrome (1), including hearing sensitivity, learning and memory, suggesting that the defects in Fragile X syndrome are not irreversible and that it may be possible to effectively treat the cognitive and behavioral disabilities by pharmacological inhibition of mGluR5.
While CTEP is not currently being developed for clinical use, the result of this trial adds further weight to the evidence in favor of mGluR5 inhibition as a means to treat Fragile X syndrome. Two other mGluR5 antagonists – Fenobam and STX 107 – are already being evaluated in early clinical trials following successful evaluation in Fmr1 knockout mice, and this most recent result should encourage further investment in this approach.
The discovery that symptoms can be reversed in established disease in a model of Fragile X syndrome that accurately models the disorder in humans is a major advance, suggesting that the impairments associates with autistic spectrum disorders may not always be permanent – a result with profound implications for the future of treatment of these disorders.
1) Michalon A, Sidorov M, Ballard TM, Ozmen L, Spooren W, Wettstein JG, Jaeschke G, Bear MF, Lindemann L. “Chronic Pharmacological mGlu5 Inhibition Corrects Fragile X in Adult Mice.” Neuron. 2012 Apr 12;74(1):49-56. PubMed 22500629