SPRING 2007 VOLUME 14, NO.1 FRAXA Research Leads to A PUBLICATION OF FRAXA RESEARCH Orphan Drug Designation FOUNDATION For the first time, a compound being developed to treat Fragile X has received an Orphan Drug Designation “ from the Food and Drug Administration (FDA). In collaboration with FRAXA, Neuropharm Group intends to develop fenobam to treat Fragile X syn- EVER N drome. Neuropharm Group PLC is a United Kingdom based pharmaceutical company focused on developing DOUBT treatments for central nervous system disorders. The FDA has granted Neuropharm an Orphan Drug Designation for the use of fenobam in Fragile X. that a small The U.S. Congress passed the Orphan Drug Act in 1983 to accelerate development of treatments for rare dis- group of eases, defined as affecting 200,000 or fewer people in DORIS BUFFETT’S the U.S. Fragile X affects almost 100,000 US residents. CHALLENGE thoughtful, Fragile X – A Disease of Excess Doris Buffett, president and founder of the Sunshine Lady Fragile X results from the lack of one protein, the Foundation, has donated committed Fragile X Mental Retardation Protein (FMRP). Without FMRP, brain cells do not communicate normally. The $500,000 to FRAXA. continued on page 2 citizens can most exciting recent research advance has been the dis- covery of a hyperactive brain pathway (mGluR5) in Fragile X animal models. Dr. Mark Bear, Director of Jim change the MIT’s Picower Institute, has called Fragile X “a disease of excess.” Studies have found excessive mGluR5 signal- Cantore ing in the brains of Fragile X animal models. The good world. Joins news is that compounds which block mGluR5 (mGluR5 antagonists) can tone down this excess, FRAXA INDEED, potentially reversing Fragile X symptoms such as learn- The Weather Channel’s Storm ing problems, anxiety, and autistic behaviors. Further Tracker Jim Cantore is on the front studies suggest this excess may also occur in other it’s the only line of hurricanes and severe weath- Spectrum Disorders. er everywhere. Jim has his own storm story too: his son Ben and thing that Also in this issue: daughter Christina have Fragile X. • $700,000 Awarded in New Research Grants Watch Jim’s 30-second video at ever has.” • Update on Drug Trial: Lithium fraxa.org, and Jim help FRAXA. continued on page 12 • Events Reports and Calendar — Margaret Mead FRAXA is a nonprofit, tax-exempt charity run by parents of children with . Fragile X syndrome is the most common inherited cause of mental retardation and developmental disabilities, affecting approximately 1 in 4000 males and 1 in 6000 females. FRAXA’s goal is to accelerate research aimed at the treatment and cure of Fragile X, by direct funding of promising research projects and by raising awareness of this disease. Report By David and Mary Beth Busby from Washington: syndrome and associated disorders. This growth of Fragile X research supported and conducted by NIH has created a need to coordinate the communication of these research efforts both within NIH and with outside advocacy groups. In response to Congressional Appropriations Committee report lan- guage, Dr. Duane Alexander, Director of the National Institute of Child Health and Human Development (NICHD), convened the first meeting of the NIH Fragile X Research Coordinating Group on March 28, 2007. Participants included representatives from NICHD, the National Institute of Mental Health, the National Institute on Aging, the National Institute of General Medical Sciences, the National Institute of Diabetes and Digestive and Kidney Diseases, the The National Institutes of Health (NIH) has 27 Institutes National Institute of Neurological Disorders and Stroke, the and other major units. Eight of them currently fund a diverse array of Fragile X research projects. The Fragile National Institute on Deafness and Other Communication X community has petitioned the Congress, and Disorders, and the National Cancer Institute. Congress has asked NIH, to improve coordination of this research. We are pleased that the first inter- Information regarding Fragile X research being supported by NIH Institute meeting was recently held. was presented and discussed at the meeting. Other topics discussed by the group included: Here’s a report by guest editor, Dr. Tiina Urv of the MRDD Branch of the NICHD. Dr. Urv is coordinator of • the development and dissemination of resources both across NIH the new NIH Fragile X Research Coordinating Group. and to advocacy groups; In recent years, a growing number of National • opportunities for collaboration and communication between the Institutes and Centers (ICs) within the National NIH institutes and with outside groups; and Institutes of Health (NIH) have been involved • future meetings of the group, including an annual meeting with with the expanding NIH research portfolio that Fragile X organizations. has contributed to our knowledge of Fragile X

Doris Buffett Challenge continued from page 1 Doris Buffett has also challenged FRAXA to raise an additional $500,000 in new money before November 1, 2007. If we suc- ceed, she will match it 100%! All Buffett Funds are designated exclusively for Fragile X research, so this would enable FRAXA to support many new projects aimed at treatment. Doris Buffett has been a close friend of Mary Beth Busby, a founding member of FRAXA’s Board of Advisors, for many years. When she read the book, Dear Megan, by Mary Beth and FRAXA Vice President Megan Massey, Ms. Buffett decided to learn more about FRAXA and its mission. An article in Worth magazine called the Sunshine Lady Foundation “uniquely hands-on, folksy, a person-to-person enterprise – the un foundation” because of Doris’ hands on, personal involvement with every aspect of the foundation’s grant-making process. Since its inception in 1996, the Sunshine Lady Foundation has awarded more than $30 million in grants. Raising $500,000 in NEW money means that we need to reach out beyond FRAXA’s loyal supporters to new people who may not have direct experience with Fragile X. By now, you should have received our special Sunshine Edition Newsletter about the Doris Buffett Challenge to FRAXA. Please help us meet the Challenge! We will be happy to provide you with brochures, flyers and other materials to spread the word.

2 FRAXA UPDATE SPRING 2007 RESEARCH OVERVIEW

FRAXA has spent almost $12 million on Fragile X research, possible points of intervention (treatment). Other promis- and one third of that total has been spent building the case ing drugs do not affect mGluR5 directly, but help to tone for using mGluR5 antagonists to treat Fragile X, starting down the excessive activity of the brain’s mGluR pathway with an award in 2000 to Dr. Mark Bear and Dr. Kimberly in other ways. This is how lithium seems to help. Huber. Several mGluR5 antagonists have been tested in The key question remains: how well will these medications Fragile X animal models (mice, flies, and zebrafish), and work for people with Fragile X? Evidence in animal mod- the compounds reverse most Fragile X symptoms that have els is encouraging, but we won’t know how well these been identified in those animals. drugs work until clinical trials can begin. Fenobam – Mystery Solved Could these drugs treat Autism? Fenobam was developed in the 1970s at McNeil It is likely that lithium, mGluR5 antagonists, and several Laboratories for anxiety disorders. In trials in hundreds of other drug classes currently under investigation will effec- patients, fenobam showed a good safety profile and some tively treat Fragile X. But they may do more. Since many effectiveness, but how it worked was a mystery (as with people with genetically unrelated Autism Spectrum many – even most – psychiatric drugs). Fenobam was Disorders appear to have defects in the same cellular path- never marketed for human use and is now off-patent. ways, they may respond to the same treatments. FRAXA is Two decades later, scientists at Roche revealed that funding studies to develop “biomarkers” – blood tests to fenobam is an mGluR5 antagonist, making it a promising identify those non-Fragile X individuals who have abnor- candidate for treatment of Fragile X. malities in the same pathways. These tests may be able to identify autism cases which are biochemically similar to Fenobam is one of many potential treatments for Fragile X Fragile X and thus likely to respond to the same treat- which we hope will emerge from the translational research ments. Thus, Fragile X is an important area for expanded FRAXA has sponsored since 1994; others are in the funding of translational research, not only because it is a pipeline. Since researchers identified basic brain pathways tractable problem, but also because it is an important test- which are disrupted in Fragile X, they have found many bed for the development of new autism treatments.

Clinical Trial Update – Lithium FRAXA is funding a trial of lithium in Fragile X patients conducted problems. No kidney problems or tremor have been seen. by Elizabeth Berry-Kravis, MD, PhD, at Rush University Medical Center in Chicago. Lithium is a mood stabilizing drug which has Although full analysis has not yet been done, it appears been in use for decades to treat bipolar disorder. Lithium has many that there was overall improvement in at least three effects on the brain, not all of which are understood, but one of its behavioral measures and at least one cognitive test. For known actions is to dampen mGluR5 activity. FRAXA-funded stud- ies in Fragile X mice and flies have shown that lithium can reverse all participants continuing treatment past five months, some symptoms of Fragile X. behavioral improvements have persisted.

by Dr. Elizabeth Berry-Kravis This small open trial suggests that lithium may be a use- ful Fragile X treatment. We hope that this trial will pro- All participants have completed two months of treatment in vide support for a larger placebo-controlled trial to fur- our lithium trial, allowing initial data analysis. An early look ther evaluate the potential and safety of lithium. at the results is encouraging. Sixteen individuals with Fragile X were enrolled, ranging A Case Study from age 6 to young adulthood. Of the 15 who completed Eric (22 yrs old) began the study in September 2006. We two months of lithium treatment, some improvement in lan- have noticed subtle changes. He is better able to commu- guage was noted by 12 families. Twelve families chose to con- nicate the events of his day and upcoming events. At our tinue treatment for a year. Of those, 11 improved in some Christmas office party, three people who don’t see him area and one was unchanged. Side effects have been mild for regularly were impressed with how he joined the group most participants, with increased thirst and urination and and held a conversation. My sister-in-law called the house one day and Eric answered. She later said how surprised mild changes in thyroid function being the most common she was when she realized she was speaking with Eric!

FRAXA 45 Pleasant Street, Newburyport, MA 01950 Phone: 978-462-1866 Fax: 978-463-9985 email: [email protected] fraxa.org 3 EDITOR’S NOTES Development of mGluR5 Antagonists to Treat Fragile X Syndrome and Autism What causes RANDALL CARPENTER, MD Fragile X? Principal Investigator F R A X A RESEARCH A gene on the X chro- MARK BEAR, PhD Co-Investigator mosome, called FMR1, Seaside Therapeutics, $10,000 Targeting MMPs to Treat Dendritic shuts down and cannot Spine Malformation & Behavioral produce its normal pro- Seaside Therapeutics was founded by Dr. Mark Defects in Fragile X Mice tein product, FMRP. Bear, Director of the Picower Institute at MIT, IRYNA M. ETHELL, PhD Principal Investigator Loss of FMRP affects and Dr. Randall Carpenter, a physician with University of California Riverside, $60,000 brain development, many years of drug development experience. leading to symptoms Seaside has received a major grant from the including learning prob- NIH, with additional funding from FRAXA and lems, anxiety, autistic Cure Autism Now (CAN). behaviors, and some- times seizures. Seaside has licensed from Merck several selec- tive, potent mGluR5 antagonists. They intend to develop the lead compound, STX107, to treat Fragile X and, potentially, autism. They will The brain is a net- advance the compound through the preclinical Douglas Ethell, Iryna Ethell, Tina Bilousova work of cells (neurons) studies necessary to fulfill FDA requirements to We are investigating how the brain’s neu- which send electrical open an Investigational New Drug application ronal network develops and how problems and chemical signals and perform initial testing in humans. with this process can cause cognitive from one to the next. impairment, with a focus on dendritic Cell-to-cell communica- The Neurobiology of Fragile X: A spines. This project will investigate the role tion occurs at synapses. Unifying Neuro-Endocrine Hypothesis of matrix metalloproteinases (MMPs) in ABDESLEM EL IDRISSI, PhD the development of abnormal dendritic spines in Fragile X. We will use an MMP Principal Investigator inhibitor, minocycline, to accelerate spine College of Staten Island/CUNY development in the brains of Fragile X $34,000 RENEWAL mice. Minocyline is an antibiotic some- Our early data shows that the times used to treat acne. expression of a protein called We hypothesize that excessive levels of somatostatin is significantly MMP activity in FMR1 knockout mice decreased in the brains of Fragile X mice. contribute to abnormali- The good news about Reduced somatostatin could account for ties and cognitive dysfunction. We propose Fragile X is that it many features of the syndrome. that inhibiting this excess MMP activity appears to effect com- We have found that adding taurine to drinking with minocycline will prevent abnormal munication between water increased somatostatin expression in the dendritic spine development and related cells, but the cells brains of both Fragile X and normal mice. The behavioral defects, effectively treating themselves may not be increase in somatostatin reversed some of the Fragile X. permanently damaged. Fragile X symptoms seen in these mice. Brain plasticity refers Cellular Processes Regulated by FMRP This raises the possibility that either somato- to the brain’s ability to During Development adapt and remodel its statin or taurine could treat Fragile X. While connections. The brain somatostatin must be infused intravenously, PETER KIND, PhD Principal Investigator taurine is an over-the-counter nutritional sup- is by far the most plas- SALLY TILL, PhD Postdoctoral Fellow tic, adaptable organ of plement (and a major ingredient in Red Bull, the body. along with a lot of caffeine). This project will University of Edinburgh, $60,000 confirm and extend the preliminary results Many of the cognitive and behavioral fea- with further trials of agents which enhance tures of Fragile X emerge during childhood somatostatin function.

4 FRAXA UPDATE SPRING 2007 development and dynamics of synapses by following individual postsynaptic den- EDITOR’S NOTES dritic spines and presynaptic axonal bou- RESEARCH tons over extended periods of time in the brains of living Fragile X mouse. We do A synapse is a junc- this by marking single neurons with tion between two neu- and are associated with abnormal organi- Yellow Fluorescent Protein. rons. A neuron receives zation of connections in the cortex. Lack signals via receptors of the protein FMRP causes the syndrome. We will determine if and when abnormal at synapses on its den- While recent work has begun to reveal structural plasticity occurs in Fragile X dritic spines: small roles for FMRP in the plasticity of adult mice. We will also test whether abnormal protrusions on the sur- brain cells, the mechanisms by which it structural plasticity of synapses can be face of its dendrites. influences development of the cortex reversed with drugs (including mGluR5 remain unclear. We are testing the hypoth- antagonists) that have been shown to cor- esis that lack of FMRP during develop- rect behavior problems in fly and mouse ment leads to abnormal cortical organiza- models of Fragile X. tion. We are focusing on the primary somatosensory cortex in a Fragile X mouse Imaging Aberrant Synaptic Structure model. This brain region is an excellent and Function in an Animal Model of system to study cortical development Fragile X because it contains easily identifiable and C ARLOS PORTERA-CAILLIAU, MD, PhD highly organized structures called “barrels” Principal Investigator which emerge and are refined through a stereotypical sequence of developmental UCLA, $50,000 RENEWAL events. We are testing the If we find that loss of FMRP results in hypothesis that a abnormal cortical development in mice, defect in dendritic Defects in dendritic we will go on to investigate whether these filopodia occurs in spines have been found abnormalities can be reversed by reducing Fragile X syndrome in the brains of patients signaling of group 1 metabotropic gluta- and impairs the ability with Autism Spectrum mate receptors (mGluRs). of these tiny protru- Disorders including sions to form synapses Fragile X and Rett and mature into In Vivo Imaging Of Synaptic Syndrome. spines. Abnormalities In A Mouse Model Of Fragile X Using two-photon microscopy, we are imaging dendritic filopodia (emerging WEN-BIAO GAN, PhD Principal Investigator spines) in the brains of anesthetized Brain Development FENG PAN, PhD Postdoctoral Fellow Fragile X knockout mice and looking for New York University, $40,000 defects in their density, length, or Neuroscientists believe dynamics. We are also investigating the that learning occurs Studies have revealed an role of group I mGluRs in glutamate- when the synapses are overabundance of long, induced filopodia growth. We intend to strengthened (Long thin dendritic spines in find a link between abnormal signaling Term Potentiation or the brains of Fragile X through mGluRs and the increased patients and knockout density and length of spines in Fragile X LTP) or weakened (Long mice, suggesting that mice. Term Depression or abnormal formation LTD) in response to Ultimately, the new knowledge derived and plasticity of neu- activity. Unneeded Wen-Biao Gan from this research may identify new treat- ronal connections play synapses are eventually important roles in causing behavioral and ment targets, including but not limited to pruned away. learning deficits. the use of drugs that modify mGluR neu- rotransmission. Using a new transcranial two-photon imaging technique, we will examine the

FRAXA 45 Pleasant Street, Newburyport, MA 01950 Phone: 978-462-1866 Fax: 978-463-9985 email: [email protected] fraxa.org 5 EDITOR’S NOTES Effect of MPEP on Neuronal and Glial Cell Specific Glutamate This process is tightly Metabolism in Fragile X regulated and depends Mouse Brain F R A X A RESEARCH on the creation of new MARY MCKENNA, PhD proteins at synapses in Principal Investigator cell membrane, to the interior of the neu- ron. Alterations in Homer cause changes in response to activity. University of Maryland, $42,000 mGluR location and function and may be Normally, the Fragile X According to the mGluR responsible for the observed increase in protein FMRP plays an theory of Fragile X, excessive mGluR activa- mGluR-LTD in Fragile X. important role in fine- tion underlies symptoms of the syndrome. This team will investigate these interac- tuning the process. Although mGluR activation involves gluta- tions with an eye toward discovering addi- mate neurotransmission, it is not known how tional treatment targets. the increased mGluR activation affects gluta- mate metabolism in brain. Since ongoing Treatment of Fragile X Syndrome via neurotransmission requires coordinated The mGluR Theory the GABA-A Receptor interactions between synapses and surround- In Fragile X syndrome, ing astrocytes that remove glutamate from FRANK KOOY, PhD Principal Investigator with FMRP absent from the extracellular space, and since mGluRs are University of Antwerp, $50,000 brain cells, growing evi- found on both postsynaptic dendrites and astrocytes, increased activation of mGluR While most studies have focused on exces- dence suggestions that could alter both neuronal- and astrocyte-spe- sive activity of glutamate pathways, notably there is excessive signal- cific aspects of glutamate metabolism. the mGluR5 pathway, there is also evidence ing through one set of of decreased function of the brain’s receptors at synapses: Our preliminary data suggests that synthesis inhibitory pathways in Fragile X. For group 1 metabotropic of glutamate, GABA and glutamine is example, 20-30% of boys with Fragile X increased in Fragile X mice and that these experience seizures, probably due to a fail- glutamate receptors alterations are normalized in mice treated ure of inhibitory pathways. (mGluRs). (To confuse with the mGluR5 antagonist, MPEP.We will matters, group 1 mGluRs determine the effects of MPEP on cell specif- The brain’s inhibitory circuitry is primarily are also known as ic alterations in glutamate, GABA and gluta- controlled by the neurotransmitter GABA. mGluR1 and mGluR5). mine metabolism in brains of Fragile X mice Naturally-occurring substances called neu- using the powerful, state of the art technique rosteroids enhance GABA function and are The mGluR theory of of nuclear magnetic resonance (NMR) spec- important for normal brain function. This Fragile X proposes that troscopy. Any alterations found in metabo- project will test whether recently developed this excessive mGluR lism may help identify new targets for thera- synthetic neurosteroids can reverse symp- activity causes too many peutic interventions. toms of Fragile X in mice. new proteins to be made. Homer and Hippocampal mGluR-LTD in Sleep and Circadian Rhythms in Fragile X Fragile X Mutant Drosophila KIMBERLY HUBER, PhD RAVI ALLADA, MD Principal Investigator Principal Investigator ELAINE MERRILL SMITH, PhD JENNIFER RONESI, P h D Postdoctoral Fellow Postdoctoral Fellow Northwestern University, $40,000 UT Southwestern, $49,000 Jennifer Ronesi Many people with Absence of FMRP results In a normal brain, FMRP Fragile X have prob- in altered function of metabotropic gluta- lems with sleep. The acts to check the synthe- Elaine Smith mate receptor (mGluR) pathways. Recent fruit fly has a gene, dfmr, sis of new proteins. studies have shown abnormalities in a pro- that is similar to the human FMR1 gene. tein called Homer in Fragile X animal mod- Flies lacking dfmr exhibit altered behaviors els. Homer links mGluRs, which sit in the consistent with the human syndrome,

6 FRAXA UPDATE SPRING 2007 covered protein as well. Because of the excit- ing discoveries centered around the mGluR EDITOR’S NOTES theory of Fragile X, we have added studies involving the inferior colliculus, a brain But in people with RESEARCH region which expresses high levels of Fragile X, FMRP is not mGluR5. Fortuitously, we can study all these present and the result including disrupted circadian rhythms. components simultaneously in neurons of is thought to be run- Circadian rhythms control the daily timing the auditory brainstem. away protein synthesis. of physiology and behavior in organisms from bacteria to humans. I have demon- Characterization of Transgenic Mouse strated that flies mutant for dfmr also have Models to Investigate the Molecular decreased sleep and poor sleep quality, just Mechanisms Underlying FMRP as is observed in humans with Fragile X. Function at the Synapse and Therapeutic Intervention in Fragile X I will test whether the altered behaviors in mutant flies can be restored with a normal ROB WILLEMSEN, PhD Principal Investigator copy of the dfmr gene introduced during Erasmus University, The Netherlands, $50,000 adulthood, or whether this gene is also RENEWAL required during development. I will also Dr. Willemsen is generating sophisticated investigate the link between dfmr and other new mouse models for Fragile X which will known genes to shed light on the normal facilitate many studies. One mouse strain mGluR antagonists activity of dfmr with regard to sleep and has an inducible fluorescent FMR1 fusion circadian rhythms. These findings may mGluR antagonists are gene. In this mouse, the FMR1 gene can be yield novel treatment targets. compounds that block switched on by adding doxycycline to the or dampen mGluR activ- animal’s feed. The mouse will then produce Characterization of Kv3.1 In Auditory FMRP which can be seen easily, since green ity. The logic behind Brainstem Nuclei In the Fragile X using mGluR antago- Knockout Mouse fluorescent protein will be produced wher- ever FMRP is present. nists to treat Fragile X is LEONARD K. KACZMAREK, PhD to restore the normal They will generate other mouse models to Principal Investigator balance of protein syn- study the role of FMRP in AMPA receptor JACK KRONENGOLD, PhD expression in neurons. This will allow fur- thesis. Drugs which Postdoctoral Fellow ther study of the mGluR theory of Fragile block mGluR1 are not Yale University, $40,000 RENEWAL X, since excessive mGluR signaling is likely treatments due to Individuals with Fragile X syndrome and thought to cause a significant decrease in side effects. However, autism spectrum disorders exhibit extreme AMPA receptor expression in Fragile X. mGluR5 antagonists like sensitivity to sounds which interferes with MPEP have been effec- attention, learning, and social interactions. Activity-Dependent Trafficking of tive in mice and other AMPA Receptor mRNAs in Dendrites This sensitivity is likely due to changes in animal models of electrical properties in neurons of the audi- R. SUZANNE ZUKIN, PhD Fragile X. tory brainstem. Our studies will define Principal Investigator abnormal sensory processing at the cellular Several pharmaceutical SHO FUJISAWA, PhD and molecular level and will likely lead to companies are currently Postdoctoral Fellow strategies for therapeutic intervention. developing mGluR5 Albert Einstein College of We have identified a new FMRP-interacting Medicine, $65,000 antagonists to treat protein which is widely expressed in neurons Sho Fujisawa Fragile X. Neuropharm in many parts of the brain. We are currently Cognitive impairments in (neuropharm.co.uk) and Fragile X may result from examining its function in the auditory brain- Seaside Therapeutics dysregulation of messenger stem and how this is likely to be misregulat- seasidetherapeutics.com, ed in Fragile X and Autism Spectrum RNA localization and local are discussed in this Disorder individuals. protein synthesis. This proj- ect aims to understand how newsletter. Our project now includes not only studies AMPA receptor mRNA Suzanne Zukin of the Kv3.1 channel but of the newly dis-

FRAXA 45 Pleasant Street, Newburyport, MA 01950 Phone: 978-462-1866 Fax: 978-463-9985 email: [email protected] fraxa.org 7 localization in dendrites is altered in Fragile X. EDITOR’S NOTES We will use molecular, biochemical and imag- ing techniques to look for possible alterations Fragile X Knockout in AMPAR mRNA trafficking in the Fragile X F R A X A RESEARCH Mouse mouse. We will also identify signaling pathways involved in regulation of dendritic targeting studies. This group is the first to study how of AMPAR mRNAs and local protein synthe- mGluRs move around in Fragile X neurons. sis and examine their possible dysregulation These receptors are not fixed but move in KO mice. A focus will be on signaling cas- around in the cell membrane, from one part cades known to be downstream of group I of a synapse to another, in ways that are tight- ly controlled. There is reason to suspect that mGluR activation and important to local absence of FMRP damages these processes. protein synthesis. Understanding these movements may lead to Defective Cyclic AMP Signaling in new targets for drug discovery and may help FMR1 knockout mice Fragile X optimize Fragile X treatments with mGluR have been genetically ANITA BHATTACHARYYA, PhD antagonists. engineered so that the Principal Investigator FMR1 gene is “knocked University of Wisconsin, $60,000 The Drosophila Model of Fragile X out” of their genome. Syndrome: Testing the Metabotropic Cells respond to signals (e.g. Glutamate Receptor Hypothesis Fragile X knockout (KO) electrical or chemical sig- mice produce no FMRP. nals) by signaling pathways KENDAL BROADIE, PhD that relay information from Principal Investigator the cell’s surface (mem- CHARLES TESSIER PhD brane) to the nucleus where changes in gene Postdoctoral Fellow expression occur. We want to test how the loss Vanderbilt University $40,000 of FMRP affects these pathways. One relay RENEWAL molecule that has been implicated in Fragile X Charles Tessier Because they show is cyclic AMP (cAMP). Fragile X researcher We are using the powerful social behaviors and Elizabeth Berry-Kravis has shown that cAMP genetic system of the fruit fly, Drosophila melanogaster, to investigate the molecular brain development is lower in blood cells from Fragile X patients. basis of Fragile X Syndrome (FXS). Mutant abnormalities similar to We have found that cells of the brain are also not able to produce cAMP as well in Fragile X. animals lacking the Drosophila Fragile X pro- those of patients with tein, dFMRP, develop characteristic FXS neu- Fragile X and some Lowered cAMP affects how FX neurons func- tion during development and during plasticity. ronal and behavioral defects. An exciting other forms of autism, hypothesis in the field suggests that FMRP these mice are excel- We want to understand why cAMP production may be regulated via metabotropic glutamate lent animal models to is lower in Fragile X. How does the lack of receptors (mGluRs). The mGluR theory sug- study the underlying FMRP cause lower cAMP signaling? Is there a gests that FMRP functions to limit neuronal link between defective cAMP production and mechanisms of the dis- activity in response to these receptors. the mGluR pathway? Using a drug assay on order and to test human FX cells, we hope to find compounds We are testing this hypothesis by using ani- potential treatments. that can rescue the cAMP defect in FX cells. mals that lack both dmGluRA and dFMRP. We are employing physiology and molecular It is even possible to Regulation of Group I Metabotropic tools to understand the roles of each protein develop mice in which Glutamate Receptor Trafficking in a in FXS. We are also using drugs that specifical- the Fragile X gene can Fragile X Animal Model ly block mGluR signaling to identify the con- be turned on or off at vergence of these two important biological any point during devel- ANNA FRANCESCONI, PhD,Principal Investigator pathways. This research may lead to develop- opment. Albert Einstein College of Medicine, $43,500 ing new drugs that specifically target mole- Abnormalities in the Fragile X brain’s mGluR cules involved in the disease and avoid those pathways have been demonstrated by many which may lead to unwanted side-effects.

8 FRAXA UPDATE SPRING 2007 and in different brain regions. We will also determine whether stimulating GABA EDITOR’S NOTES receptors alters FMRP methylation, or other locally synthesized proteins in den- Fragile X Fruit Flies RESEARCH drites. We hope to further our understand- Remarkably, scientists ing of the role FMRP plays in normal cel- have have made great lular metabolism. Specific Tests of the mGluR Theory of Fragile X: High-throughput FMRP-MAP1B RNA interactions in Determination of Synaptic Protein Fragile X Changes in the FMR1 KO Mouse MIHAELA RITA MIHAILESCU, PhD PETER discoveries about com- Principal Investigator plex disorder like VANDERKLISH, PhD Duquesne University, $45,000 RENEWAL Principal Investigator Fragile X by studying The Fragile X Protein, FMRP, is thought to the lowly fruit fly. Institute, San repress translation of specific messenger Diego The fly’s simplicity is its $50,000 RENEWAL RNAs (mRNAs) within cells. FMRP stops power. The fly genome is mRNA from being translated into protein easily manipulated, and The most critical gap in until the appropriate signal occurs, indicat- our understanding of Fragile X is the identifi- ing the right time to make a protein. a wide range of Fragile cation of proteins that are dysregulated in the X fruit fly models have absence of FMRP. This team is investigating the effects of mod- been genetically engi- ifications of FMRP on its interactions with neered. Fragile X flies We use high throughput proteomic techniques RNA targets, particularly MAP1B which is to understand how the absence of FMRP important because several studies have exhibit symptoms, such affects levels of other proteins in neurons. We shown that it is misregulated in Fragile X. as sleep disorders and have identified several proteins that may con- learning problems. Flies tribute to the abnormalities in synaptic shape FMRP as a Modulator of Dendritic breed quickly and adapt seen in Fragile X and a few proteins that have mRNA Translation in Response to well to laboratory life. been implicated in autism. One protein pres- Metabotropic Glutamate ents a potential opportunity for therapeutic intervention with drugs that are currently in GARY BASSELL, PhD Principal Investigator clinical trials for unrelated indications. RAVI MUDDASHETTY, P h D Researchers and Postdoctoral Fellow, Emory University, $40,000 Effects of Alternative Splicing at FMR1 Parents Exon 15 on Understanding Fragile X FMRP modulates dendritic mRNA transla- Since 1994, FRAXA has Syndrome tion in response to mGluR activation. An understanding of how the process may be funded over $11 million ROBERT DENMAN, PhD Principal Investigator dysregulated in FXS is essential to under- in Fragile X research New York State Institute for stand the function of FMRP. conducted by scientists Basic Research, $57,500 I will study mRNA targets of FMRP using around the world. While we often speak of synaptoneurosomal preparations and cul- Perhaps the most FMRP as a single protein, it tured hippocampal neurons in the FMR1 remarkable discovery is actually a set of related KO mouse. Agonists to mGluR and NMDA we have made is that isoforms (proteins) made receptors will be used to determine a role many scientists are also by alternate splicing of its mRNA. These for FMRP in either or both pathways. We proteins can also be modified in a number parents – or brothers or will also assess the ability of the mGluR5 of ways, such as phosphorylation and sisters – of children antagonist, MPEP, to correct alterations in methylation. The activity of FMRP is the with Fragile X or relat- dendritic mRNA translation in cultured sum of all of the isoforms in their various ed disorders. For these neurons from mice. modified states. scientists, the potential We believe that our work will help in We seek to understand the role these of this important work screening potential therapeutic compounds processes play during brain development is especially clear! to target Fragile X.

FRAXA 45 Pleasant Street, Newburyport, MA 01950 Phone: 978-462-1866 Fax: 978-463-9985 email: [email protected] fraxa.org 9 FRAXA is a grass-roots organization, found- ed in 1994 by parents and run by parents. FRAXA depends on families and friends for RAISING FUNDS AND AWARENESS the funds that drive progress towards a cure for Fragile X. Check fraxa.org often for a listing of upcoming events.

Please take a moment to give to FRAXA by where they spoke further phone: 978-462-1866, fax: 978-463-9986 or with him about Fragile X online at fraxa.org. All major credit cards and FRAXA. accepted. Your donation matters! A raffle was held to benefit FRAXA. The audience was overjoyed when none other than Ara Bagdasarian won Front row, left to right: 2Lt. Dorian Sherman, Capt. Giuseppe Scaglione, Capt the $10,000 grand prize! Teodoro Apolisok. 2nd row: 2Lt. Patricia Lowry, Capt. Kwibisa Muyunda (Zambia), Mr. David Sturgell, Capt. Todd Dye, 2Lt. Hamad Rejairan (Bahrain) , Ara and Leslie donated 2Lt. Brian Krusemark, 2Lt. Josephine Beacham, 2Lt. Andy Glindmeyer, their prize back to FRAXA, 1Lt. Abdullah Isa Almaeeli (Bahrain), 1Lt. Abdulrahman Aloun (Bahrain). Back row: 2Lt. Ben Lowry, 2Lt. Aaron Pauli, 2Lt. Trevor Johnson, Capt Andrew Holko. and in combination with Fragile X Shares the Stage the other contributions, the Marathon for Fragile X with Former President total raised for FRAXA was $45,000! George H. W. Bush Alexa Jaccarino, a member of the class of Since 2003, the First Data Western Union Air Force Officers Fundraiser 2008 at Stonington High School in Foundation and TravelCenters of America Pawcatuck, CT, ran a half marathon in New have supported FRAXA with a joint annual Renee Butler’s son Brian Krusemark York City. She decided to run the race in $50,000 donation. Ara Bagdasarian, attended a 14-week aircraft maintenance honor of her friend Dave Clark, Jr. trustee of the Fragile X Alliance of Ohio, is course at the Sheppard Air Force Base in a marketing executive for TravelCenters of Alexa writes “I proudly crossed the finish America. Ara’s wife Leslie is a FRAXA Texas. The officers learned how to manage board member, and 14-year-old Julie and various aircraft, including fighters, bombers, line in two hours and forty six minutes 12-year-old Alex both have Fragile X. cargo planes, and refueling platforms. They with the knowledge that I was helping also learned about avionics, hydraulics, millions of children through your extremely Last Fall, Ara and Leslie Bagdasarian were electrical systems, and more. valuable organization.” Congratulations, asked to share their own Fragile X story at Alexa! the Outlook Leadership Conference in In their free time, the officers delivered Phoenix, Arizona, an event attended by Meals on Wheels, built homes for Habitat Pittsburgh Zone Team over 700 executives from the convenience for Humanity, and sold breakfast burritos store industry. FRAXA was chosen as the for charity. Two thirds of the burrito funds In November, the Pittsburgh Zone Sales conference-featured charity by The were donated to the Air Force Aid Society. Team from Kellogg’s Snacks held a Chinese Children’s Leadership Foundation. Students made presentations to the class to Auction to benefit FRAXA at their annual determine to whom they would donate the Holiday Party. With over 140 employees Ara described their family’s experiences of remaining $400. Second Lt. Brian and spouses in attendance, over $1200 diagnosis and living with Fragile X and Krusemark advocated for FRAXA. Brian’s was raised. Many thanks to Zone their hope for a future cure or treatment. younger Manager, Tom Beal, for all his support. He discussed FRAXA’s mission and progress brother Adam Kellogg’s Snacks had previously donated and showed the video “First Down Towards has Fragile X four tickets to their Pittsburgh Steelers’ a Cure.” The audience gave Ara a standing Syndrome. suite for FRAXA’s X Ball gala, raising an ovation and generously gave to our cause. additional $2500. Over 100 President George H. W. Bush viewed people A Bowling Birthday FRAXA’s video and heard the Bagdasarians’ attended the story. Mr. Bush, who spoke immediately On March 17, Franziska Klebe and her graduation and following Ara, remarked on Fragile X and husband Chuck Samuelson hosted a presentation Adam and Chris Krusemark stressed the importance of supporting this FRAXA bowling fundraiser in New York ceremony, where David Sturgell of Plano worthy cause! Ara and Leslie then attended City in honor of Franziska’s 40th birthday. accepted the check on behalf of FRAXA. a private reception with the President In lieu of gifts, guests were asked to

10 FRAXA UPDATE SPRING 2007 S AND AWARENESS

donate $2 per Fragile X. I loved the sense of hope that was pres- strike and $1 ent Saturday night – and also the joy the parents per spare expressed as they celebrated their children’s thrown. strengths. These kids who have Fragile X are spe- Calendar Notwith- cial in the best, most positive sense of that standing the word!” Check often at fraxa.org complete lack FRAXA Investigator Dr. Richard Paylor gave an EVENTS section of bowling entertaining summary of research underway at Patrick’s Pals XI talent, every- Baylor College of Medicine, and Dr. Jay Gibson Cambridge, MA one’s generosi- represented the Fragile X research team at the Sunday, June 2 ty resulted in University of Texas at Southwestern. Singer Nancy raising over Fauber-Hoh gave a delightful performance.The Play or watch the three-on- $16,000 for evening raised over $18,000 for FRAXA. three Basketball Tournament FRAXA! A great time was had by all and at 9am at the Buckingham Contribution in honor of the Franziska loved her favorite shoes-inspired Browne & Nichols School in Eddys cake! Cambridge, MA. Contact For many years, FRAXA Board member Leslie Jimmy Vershbow at Texas Bash Eddy and her husband Trevor, of Marblehead, [email protected] or To celebrate FRAXA Fall Fling 2006, FRAXA MA, have shared their experiences with Fragile X 617-924-7560. Advisory Board and FRAXA with their close member Susan Texas Residents: friends and neighbors, Cohen and her Kathy Sidford and Ted Bike Run friends Lainie If you shop at any Randalls or Tom Truscott. After Kathy and New Castle, Delaware Thumb supermarket, you can raise Gordon and Ted learned about the Sunday, July 22 money for FRAXA by using your David Mincberg mGluR Theory of Fragile X Remarkable Card. The first time you Celebrate National Fragile X hosted a festive and met the author of the use it, give the cashier FRAXA’s num- Awareness Day at our Bike evening in theory, Dr. Mark Bear, they ber: 3715. Present the card each time Run and BBQ with live band Bellaire, Texas. decided to pledge $150,000 you shop, and 1% of your purchase and silent auction. Contact Susan’s friend in contributions to FRAXA, will automatically be donated to Jen Nardo at in honor of the Eddy Family. Elaine Scott cap- FRAXA. Please share this news with [email protected] or tured the magic your friends in Texas! As if that were not gener- 302-234-7854. of the evening: ous enough, when Ted “Parker and I both agreed it was the best learned of Doris Gala – Marblehead, MA charity event we have ever attended. I loved Buffett’s Challenge to Thursday, October 4 the intimacy of the setting; we were able to FRAXA, he decided to mix and mingle and learn much about contribute an addi- The Buffett Cup Challenge tional $20,000 toward will be held at the FRAXA’s Buffett Cup Corinthian Yacht Club on Challenge in Alison Eddy the coast in Marblehead, Marblehead, on October 4th. MA. This is the height of foliage season in New Jeans Day England and space is limited, We are grateful to the employees of Levi, Ray & so reserve your table now. Shoup, in Springfield, Illinois, who raised $806 Contact Katie Clapp at [email protected] or Dr. Richard Paylor, Dr. Jay Gibson, Debbie Stevenson, for FRAXA through a casual dress-down day at David Busby, Tanya and Warren Robinson, the company. Katie Clapp, Susan Cohen, Mary Beth Busby

FRAXA 45 Pleasant Street, Newburyport, MA 01950 Phone: 978-462-1866 Fax: 978-463-9985 email: [email protected] fraxa.org 11 Storm Tracker Jim Cantore Speaks out for FRAXA E D I T O R : Katie Clapp, MS The Weather Channel’s Storm Tracker Jim CONTRIBUTING EDITORS: David Busby Cantore is on the front line of hurricanes and Mary Beth Busby severe weather everywhere. Jim has his own Mary Beth Langan storm story too: his son Ben and daughter Sally Nantais Christina have Fragile X. C O N T R I B U T O R S : FRAXA Event Hosts Research Grantees We are very pleased to welcome Michael Tranfaglia, MD Jim Cantore as the newest member of FRAXA’s D E S I G N : Mary Lou Supple Board of Directors. All FRAXA Directors are par- © 2007 FRAXA Research Foundation. All rights reserved. This ents of children affected by Fragile X. newsletter is published regularly and sent to all supporters of FRAXA Research Foundation. Jim reflects on the years when Christina and Ben were diagnosed with Fragile X: Ben “I love my life as a Storm Tracker. It’s something I wanted to do PLEASE HELP from the time I was a kid, but there’s a downside. I’ve watched hurricanes devastate whole parts of the country, and it’s tough to have to watch as the lives of families are torn to pieces. I can empathize with the emotional toll it takes on people. Talk about a change in forecast. In a few short years, our lives had gone from full of sunshine to dark and ominous, as if two storm systems had collided FRAXA is a national 501(c)(3) tax-exempt organization run by parents of children with Fragile X. overhead. Christina FRAXA’s overhead is 5%, one of the lowest of all char- My family lives in a category five state of crisis – the invisible itable organizations. Supporters receive this newsletter storm felt by other families with children who have Fragile X.” and are welcome to participate as active volunteers.

Jim decided to become active in FRAXA to increase awareness of Fragile X and raise funds for research aimed at finding a cure. Yes, I would like to help FRAXA Jim’s Public Service Announcement is now airing on Comcast o Member ($25+) o Benefactor ($500+) Cable stations on the eastern seaboard. Watch Jim’s 30-second Donor ($50+) Research Underwriter ($1000+) video at fraxa.org, and help FRAXA spread the word about o o Fragile X by sending the video to your friends and family. Contact o Sponsor ($100+) o Named Research Fund ($5000+) your local cable and radio stations and ask them to air this Public o Named Research Chair ($25,000+) Service Announcement. Send checks to: FRAXA, 45 Pleasant St., Newburyport, MA 01950 or donate online at fraxa.org

NONPROFIT ORG. U.S. POSTAGE PAID W. NEWBURY, MA PERMIT NO.59