WINTER 2008 VOLUME 15, NO.1 UPDATE A PUBLICATION OF FRAXA RESEARCH FOUNDATION “NEVER doubt that a small group of thoughtful, committed citizens can change the world. Indeed, Clinical Trials of it’s the only thing that ever has.” Fenobam Have Begun! — Margaret Mead FRAXA Research Foundation and Neuropharm, Fenobam is now being tested in an initial Phase II study in a British specialty pharmaceutical company adult males and females with Fragile X. This study is being (www.neuropharm.co.uk), are working together to explore conducted by Dr. Randi Hagerman at the UC Davis MIND the potential of fenobam to treat Fragile X and autism. Institute and Dr. Elizabeth Berry-Kravis at Chicago’s Rush Fenobam is a compound which reduces mGluR5 activity, University. Since mGluR5 antagonists have not been given which is known to be overactive in Fragile X. to people with Fragile X before, this first study uses a Fenobam was developed in the 1970s for anxiety single dose of fenobam. The outcomes of this very short- disorders. It was given to hundreds of people in clinical term investigation will determine the feasibility of longer- trials with a good safety record; however, fenobam was term studies with fenobam in Fragile X. never marketed and is now off-patent. No one knew how Robert Mansfield, Neuropharm’s CEO, commented: fenobam worked in the ‘70s; two decades later, scientists “We are delighted to announce the commencement of this discovered that fenobam blocks mGluR5 – making it of clinical study in Fragile X Syndrome. The work of FRAXA great interest to the Fragile X research community. and researchers such as Dr. Mark Bear has highlighted the Neuropharm secured US Orphan Drug Designation potential of mGluR5 receptor antagonists such as fenobam for fenobam in early 2007. In November ‘07, Neuropharm for this patient group. Professors Hagerman and Berry- submitted an Investigational New Drug (IND) application Kravis are world leading experts in the clinical study of to the FDA to gain permission to conduct human trials Fragile X and their trial of this targeted treatment is a in the United States. A month later, the FDA gave milestone for those affected by Fragile X Syndrome.” Neuropharm the green light to start human trials. For updates on this program, please sign up for email An initial Phase I fenobam trial in healthy volunteers news at fraxa.org or visit the websites ClinicalTrials.gov or in Nebraska was successfully completed in January. neuropharm.co.uk. THANK YOU FOR FRAXA’S Meet FRAXA’s BEST YEAR EVER! New EVENTS, PICTURES AND Honorary DETAILS Board See page 8 Members Dan Grimaldi, of “The Sopranos,” and Reiko Aylesworth, See page 6 of “24”, at FRAXA’s New York City Gala FRAXA Research Foundation is a nonprofit, tax-exempt charity run by parents of children with Fragile X syndrome. Fragile X syndrome is the most common inherited cause of mental retardation and autism, affecting approximately 1 in 4000 males and 1 in 6000 females. FRAXA’s mission is to fund research aimed at finding effective treatments and a cure for all children and adults with Fragile X. WANT FASTER UPDATES? RESEARCH ADVANCES Get realtime updates by joining FRAXA’s free email list at Correcting Fragile X in Mice www.FRAXA.org Scientists have reversed key symptoms of two copies of the gene for mGluR5, and therefore had only half Fragile X in mice by reducing the amount of the normal amount of mGluR5 expressed in their brains. a single protein in their brains. The protein "We decided to reduce the mGluR5 levels by 50 percent to is mGluR5 – a prime target for developing reflect what might be a therapeutically relevant condition that new drugs to treat Fragile X, and possibly would be achievable with carefully titrated drug treatment," said autism, in humans. Bear. "Total knockout of mGluR5 has deleterious effects, whereas MIT researchers led by Dr. Mark Bear, reducing it by half is innocuous." along with Dr. Sumantra Chattarji, of India’s Like many humans with Fragile X, mice lacking FMRP have National Center for Biological Sciences, seizures, impaired memory, and accelerated early body growth. published their study, “Correction of Fragile X Syndrome in Mice,” in the December 20, 2007 issue of the journal Neuron. It was FRAGILE X KNOCKOUT MICE partially funded by FRAXA, which has supported the work of Dr. Bear and col- To create a mouse model for Fragile X Syndrome, leagues at MIT every year since 2000 and researchers have bred a knockout mouse which also funds Dr. Chattarji. The study received worldwide media attention because of the lacks the gene (FMR1) encoding FMRP. These mice possibility that it could help unravel the lack FMRP, and they show several characteristics of mysteries of autism. The findings support the theory that Fragile X Syndrome Fragile X in people: changes in neuron structure, stems from too much activation of one of the brain's chief seizures, and learning impairments. network managers – the metabotropic glutamate receptor mGluR5. People with Fragile X lack a single protein, FMRP. This study found that FMRP and mGluR5 are at opposite ends of a But when mGluR5 was diminished in the Fragile X mice, these kind of molecular seesaw. They keep each other in check, and problems went away. without FMRP, mGluR5 signals run rampant. Reducing mGluR5 also reversed additional brain abnormal- The scientists were able to correct symptoms of Fragile X in ities in mice. The total rate of protein synthesis, normally Fragile X knockout mice. These mice lack FMRP and therefore excessive in the brains of Fragile X knockout mouse, was have runaway mGluR5 activity. Using genetic engineering, the reduced to normal levels. With less mGluR5, the brain of each researchers created Fragile X mice that also lacked one of the mouse no longer formed excessive neuronal connections. The mice did not have the high density of dendritic spines that is THE mGluR THEORY OF FRAGILE X characteristic of Fragile X Syndrome. In this study, researchers used genetic engineering to reduce People with Fragile X lack a protein called mGluR5, but the same thing could be accomplished by a drug. Fragile X Mental Retardation Protein (FMRP). In Pharmaceutical companies have already developed experimental the brain, FMRP normally regulates the action of mGluR5 antagonists, like fenobam, and clinical trials in Fragile X patients are underway (see page 1). a neural receptor (a kind of protein) called These findings may also lead to further targets for drug mGluR5. FMRP and mGluR5 keep each other in discovery, since scientists are now investigating drugs which check, like a molecular seesaw. affect other elements of the brain’s mGluR pathway. It should be possible to identify biomarkers – substances which can be Without FMRP, as in Fragile X, the mGluR5 measured in the blood – which can identify changes in the receptor becomes overactive, resulting in an over- function of the mGluR pathway in people with developmental production of various proteins that ultimately dis- disorders. Biomarkers may enable us to identify people with autism and related disorders who do not have Fragile X, but do rupt normal brain function and learning. This has have abnormalities in this pathway. It is likely that these individu- become known as the mGluR theory of Fragile X. als would respond to many of the treatments now being developed for Fragile X. Pictures: Dr. Mark Bear; Dr. Sumantra Chattarji 2 FRAXA UPDATE Spring 2008 Where Are We Now? By Michael Tranfaglia, MD Basic research funded by FRAXA has greatly enhanced our AVAILABLE TREATMENTS understanding of Fragile X. The field has now progressed to the Armed with detailed knowledge of the cellular defects causing point where multiple treatment strategies are being pursued by Fragile X, researchers have also identified available drugs which clinical researchers and pharmaceutical companies around the can help restore normal function. world. Translational and preclinical research projects funded by Lithium, an available agent widely used in psychiatry, has FRAXA have demonstrated the efficacy of potential treatments been shown to reverse many features of Fragile X in fly and in Fragile X animal models, and human trials are beginning with mouse models. Clinical trials in children and adolescents with several of these agents. Fragile X were conducted last year by Dr. Elizabeth Berry-Kravis at Rush University in Chicago, funded by FRAXA. Results in this A KEY DISCOVERY small open trial were promising; a paper detailing the results is The most exciting discovery yet is that excessive mGluR5 expected to be published soon, and larger-scale placebo- signaling is a major cause of Fragile X syndrome. Compounds in controlled trials are being considered. development by some pharmaceutical companies can block In addition to lithium, FRAXA-funded investigators have mGluR5, and these drugs (mGluR5 antagonists) have been found that the available drugs baclofen, taurine, and minocycline shown effective in Fragile X animal models. This has not gone all demonstrate therapeutic efficacy in Fragile X animal models. unnoticed by the pharmaceutical industry: several companies FRAXA is currently helping to organize clinical trials of all have decided to develop mGluR5 antagonists for Fragile X. three. These medicines have long histories of safe use in people. TOWARD CLINICAL TRIALS IMPLICATIONS FOR AUTISM The first company to announce a drug development program Several drug classes currently under investigation may make a for Fragile X was Seaside Therapeutics (see page 4). Next, real difference in the lives of children and adults affected by Neuropharm, a British company, announced that they would Fragile X. But they may do even more. Since many people with develop fenobam for Fragile X, in collaboration with FRAXA genetically unrelated autism spectrum disorders appear to have (see page 1).