The Theory Which Drives the Research into a Cure for Fragile X

A little history: (the following content is from the www.fraxa.org website:)

Development of the mGluR Theory

• 1997… FRAXA investigator and scientific advisor Dr. William Greenough reports that FMRP, the fragile X protein, is synthesized in dendrites in response to synaptic activity and stimulation of metabotropic glutamate receptors (mGluRs).
• 2000… In a FRAXA-funded research project started at Brown University, Drs. Mark Bear and Kim Huber discover that one mechanism of communication between neurons is defective in mice which have been bred to model Fragile X. This mechanism, called long-term depression (LTD), is a form of synaptic plasticity, the molecular basis of learning and memory. The team studied one specific form of LTD which occurs only if and when mGluRs are stimulated. They found that mGluR-LTD is excessive in the Fragile X knockout mouse.This discovery revolutionizes our understanding of Fragile X and autism. Follow-up experiments have led to the “mGluR Theory” of Fragile X: that exaggerated signaling in mGluR pathways underlies many cognitive, behavioral, and neurological symptoms of Fragile X (and probably autism, too.)
• 2001… With FRAXA funding, Dr. Robert Bauchwitz of Columbia University tests the mGluR Theory by treating Fragile X mice with MPEP, a compound which blocks mGluR5. According to the theory, this should reverse the major symptoms of Fragile X. In mice, the simplest symptoms to test are hyperactivity and sound-induced seizures. It works: a single low dose of MPEP reverses both symptoms.
• 2002… Dr. Mark Bear introduces the mGluR Theory at FRAXA’s Banbury Conferenceat Cold Spring Harbor Laboratory, spurring other researchers to follow up on this discovery. Fragile X is now becoming accepted as the first known disease of “synaptic plasticity.”
• 2003… A University of Pennsylvania team led by Dr. Tom Jongens demonstrates that fruit flies with a mutated Fragile X gene have learning deficits and that MPEP can reverse the deficits, even when given to adult flies. The team shows that the Fragile X flies have abnormal brain anatomy, which can also be corrected by treatment with MPEP during development. Further studies demonstrate that lithium, which inhibits mGluR signaling pathways, also rescues Fragile X fly anatomy and cognition. FRAXA commissions further studies at the Bauchwitz lab at Columbia, which confirm that lithium can treat seizures and hyperactivity in Fragile X mice.

• 2004… FRAXA-funded researcher Dr. Robert Wong at SUNY Downstate demonstrates that Fragile X knockout mouse brain slices have abnormally highseizure activity. He shows that this seizure activity occurs only if mGluR5s are stimulated and that MPEP can block it.
• 2005… Dr. Peter Vanderklish of Scripps, a FRAXA-funded investigator, shows a distinct pattern of abnormal protein synthesis in Fragile X neurons. This pattern immediately normalizes with brief MPEP treatment.
• 2005… FRAXA funds a clinical trial of lithium in Fragile X patients, run by Dr. Elizabeth Berry-Kravis.
• July 2005… Researchers at Hoffman LaRoche report that fenobam, a compound used in Phase II/III human trials from 1978-82, is a selective mGluR5 antagonist. In these trials, fenobam showed efficacy for treatment of anxiety disorders, but it was never tested in patients with Fragile X. Its patent has expired, so it can be tested at will.
• December 2005… FRAXA contracts with Scynexis to synthesize fenobam for experimental basic research and makes test batches available to qualified researchers free of charge.
• December 2007… Dr. Mark Bear, Dr. Gul Dolan, and colleagues publish a definitive validation of the mGluR Theory in Neuron (Correction of Fragile X Syndrome in Mice). They generated Fmr1 mutant mice with reduced mGluR5 expression and studied a range of symptoms relevant to the human disorder. They were able to correct 4 out of 5 features of the disorder.
  They note: “Fragile X is a disorder of excess — excessive sensitivity to environmental change, synaptic connectivity, protein synthesis, memory extinction, body growth, and excitability — and these excesses can be corrected by reducing mGluR5 … These findings have major therapeutic implications for FXS and autism.”
• June 2010… FRAXA builds collaborations with several of the largest pharmaceutical companies and several of the smallest startup companies to bring treatments for Fragile X into clinical trials. We are developing clinical trial sites, as well as improved biomarkers and outcome measures, which will make future trials more effective. We will continue to develop the capacity necessary to advance potential therapies through clinical trials and into routine use.