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Saturday, March 22, 2008

Fragile X Syndrome

Saturday, March 22, 2008

Today...

I am reading new post on fraxa foundation that effective treatments and a cure for all children and adults with Fragile X will be 'in front our eyes', by directly funding the most promising research.

Researchers are optimistic that the mGluR Theory of Fragile X will lead to treatments for Fragile X and for autism.
What is about mGluR theory ? OK lets me give you this references :

Development of the mGluR Theory :
  • May 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).

  • Nov. 2000 In a FRAXA-funded research project started at Brown University, Drs. Mark Bear and Kim Huber make the important discovery 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 has enormous implications for our understanding of Fragile X and related autism spectrum disorders. It and 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.)

  • May 2001 With FRAXA funding, of Columbia University tests the mGluR Theory by treating Fragile X mice with MPEP, a compound which blocks one kind of metabotropic glutamate receptor (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. MPEP is found to reverse these symptoms with a single low dose in Fragile X mice.

  • April 2002 The mGluR Theory is introduced at FRAXA's Banbury Conference on Fragile X at 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." Yearly Banbury meetings have since recruited some of the world's top neuroscientists to the study of Fragile X.

  • 2003 A team led by Dr. Tom Jongens of the University of Pennsylvania demonstrate that fruit flies with a mutated Fragile X gene have learning deficits and that MPEP can rescue these abnormalities, even when given to adult flies. The team subsequently 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 an available drug, lithium, which inhibits mGluR signaling pathways, also rescues Fragile X fly anatomy and cognition. FRAXA then commissions further studies at the Bauchwitz lab at Columbia, which confirm that lithium can treat seizures and hyperactivity in the Fragile X mouse model.

  • 2004 FRAXA-funded researcher Dr. Robert Wong at SUNY Downstate demonstrates that isolated slices of Fragile X knockout mouse brain have more seizure activity than normal mouse brain. He shows that this seizure activity occurs only if mGluR5s are stimulated and shows also that MPEP blocks it.

  • February 2005 Dr. Peter Vanderklish of Scripps Institute, a FRAXA-funded investigator, shows a distinct pattern of abnormal protein synthesis in Fragile X neurons. This pattern immediately normalizes with brief MPEP treatment.

  • July 2005 FRAXA funds a clinical trial of lithium in Fragile X patients, run by Dr. Elizabeth Berry-Kravis at RUSH University, Chicago.

  • 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 now 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.

  • January 2006 FRAXA is now actively collaborating with several of the largest pharmaceutical companies in the world and several of the smallest startup companies to bring treatments for Fragile X into clinical trials. FRAXA is developing clinical trial sites, as well as improved biomarkers and outcome measures, which will make future trials more effective. FRAXA is also funding the testing of available medications like lithium, which may have been overlooked in the past as potential treatments for Fragile X. We will continue to develop the capacity necessary to advance potential therapies through clinical trials and into routine use.
Taken from Fraxa.org.

I also got newsletter form fraxa that phase II human trial of Fenobam is underway.
Here is the newsletter :

"In December we announced that an initial Phase 1 trial of fenobam in normal volunteers had started. That trial has been completed successfully, and a Phase II trial of fenobam in patients with Fragile X has begun.

Neuropharm and FRAXA Research Foundation are working together to explore the potential of the mGluR5 antagonist fenobam to treat Fragile X Syndrome. Neuropharm, a speciality pharmaceutical company focused on neurodevelopmental disorders, received Orphan Drug Designation in November 2006 for fenobam to treat Fragile X, after acquiring rights to relevant data on the compound from FRAXA. The Orphan Drug Act aims to speed up development of treatments for rare diseases, defined as affecting 200,000 or fewer U.S. residents, like Fragile X.

Fragile X Syndrome is the most common inherited cause of mental impairment and autism. Its symptoms include intellectual handicap, hyperactivity, attention problems, autistic features, emotional liability and epilepsy. There is currently no effective treatment for the condition.

This Phase II trial is being conducted in the US by Professor Randi Hagerman from the UC Davis MIND Institute (www.ucdmc.ucdavis.edu/mindinsti tute/) and Professor Elizabeth Berry-Kravis from Rush University Medical Center ( www.rush.edu/). Since mGluR5 antagonists have not been given to people with Fragile X before, this first study will use a single dose of fenobam in each patient. The outcome of this investigation will determine the feasibility of longer-term studies with fenobam.

Robert Mansfield, Neuropharm's CEO, commented: "We are delighted to announce the commencement of this study with Professors Hagerman and Berry-Kravis who are world leading experts in the clinical study of Fragile X Syndrome. Their trial of NPL-2009 (fenobam), a targeted treatment for Fragile X Syndrome, is a milestone for those affected by this condition. This study follows the work of FRAXA, and researchers such as Dr. Mark Bear, which has highlighted the potential of mGluR5 receptor antagonists for this patient group."


Lets pray together, may it will be success soon..



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