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Fragile X and Autism-Related Disorders
Gordon Research Conference

New Insights into Disease Mechanisms Leading to Improved Therapeutics for Neurodevelopmental Disorders

Dates

June 5-10, 2016

Location

Mount Snow
West Dover, VT

Organizers

Chair:
Michael R. Tranfaglia

Vice Chair:
Peter Kind

Meeting Description

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability and the most frequent single gene cause of autism, affecting approximately 1 in 4,000 males and 1 in 6,000 females. Autism spectrum disorders (ASD) occur in up to 2/3 of males and 1/3 of females with FXS. Since the Fragile X gene (FMR1) was cloned in 1991 a large field has grown with more than a hundred labs using techniques from biochemistry through genetics to model organisms to elucidate the functions of the FMR1 protein (FMRP). FMRP has traditionally been thought of as an RNA-binding protein that regulates the translation of a set of messages highly enriched for synaptic proteins in response to neural activity, causing synapses to strengthen or weaken with experience. More recently, other distinct functions of FMRP apart from RNA binding have been discovered which implicate this protein as a major regulator of synaptic plasticity via several mechanisms. A major goal of this meeting will be to explore new FXS disease mechanisms such as channelopathies, extracellular and retrograde signaling abnormalities, and glial dysfunction.

It has become clear that in addition to the clinical overlap between FXS and autism spectrum disorders (ASD), there is likely substantial overlap in the molecular pathology of the two disorders. Molecules aimed at targets in these shared pathways are now being developed and tested in academic and pharma laboratories. It is expected that many of these targeted treatments will have therapeutic overlap in subsets of individuals with ASD or neurodevelopmental disorders (NDD). This conference will bring together leading scientists and clinicians in the Fragile X, ASD, and NDD fields, particularly those working on forms of ASD/NDD with dysfunctions in molecular pathways that overlap those implicated in FXS.

Related Meeting

This GRC was held in conjunction with the "Fragile X and Autism-Related Disorders" Gordon Research Seminar (GRS). Refer to the associated GRS program page for more information.

Contributors

Final Meeting Program

Sunday
2:00 pm - 9:00 pmArrival and Check-in
6:00 pmDinner
7:30 pm - 7:40 pmWelcome / Introductory Comments by GRC Site Staff
7:40 pm - 9:30 pmKeynote Session: Translating Neuroscience into Therapeutics
Many recent findings have shed light on the mechanisms of disease in fragile X and other autism spectrum disorders, yet therapeutic advances have proven elusive. This session will explore the challenges ahead and possible routes to enhanced clinical outcomes.
Discussion Leader: Laura Mamounas (National Institute of Neurological Disorders and Stroke, NIH, USA)
7:40 pm - 8:05 pmKimberly Huber (University of Texas Southwestern Medical Center, USA)
"Mechanisms of Sensory Circuit Hyperexcitability in Fragile X Syndrome: Implications for Therapeutics and Biomarker Development"
8:05 pm - 8:15 pmDiscussion
8:15 pm - 8:40 pmMark Bear (Massachusetts Institute of Technology, USA)
"Novel Targets for Treatment of Dysregulated Protein Synthesis in Fragile X"
8:40 pm - 8:50 pmDiscussion
8:50 pm - 9:20 pmRicardo Dolmetsch (Novartis Institutes for BioMedical Research, USA)
"Developing New Therapies for Neurodevelopmental Diseases"
9:20 pm - 9:30 pmDiscussion
Monday
7:30 am - 8:30 amBreakfast
9:00 am - 12:30 pmThe Molecular Genetics of ASDs and Targets of FMRP
FMRP regulates the translation of many other proteins, and there appears to be great overlap between the RNA binding targets of FMRP and candidate genes for autism. Here we examine the latest findings on this overlap.
Discussion Leader: Joel Richter (University of Massachusetts Medical School, USA)
9:00 am - 9:35 amKirsty Sawicka (Rockefeller University, USA)
"Translational Regulation by FMRP: Targets and Mechanism"
9:35 am - 9:45 amDiscussion
9:45 am - 10:20 amDavid Nelson (Baylor College of Medicine, USA)
"FMR1 Functions: Comparisons to Other Genetic Forms of ID/ASD"
10:20 am - 10:30 amDiscussion
10:30 am - 11:00 amCoffee Break
11:00 am - 11:35 amSuzanne Zukin (Albert Einstein College of Medicine, USA)
"Dysregulation of AMPA Receptor mRNA Targeting to Dendrites and Transcription in Fragile X"
11:35 am - 11:45 amDiscussion
11:45 am - 12:20 pmJoseph Buxbaum (Icahn School of Medicine at Mount Sinai, USA)
"From Gene Discovery to Novel Therapeutics in Phelan McDermid Syndrome"
12:20 pm - 12:30 pmDiscussion
12:30 pmLunch
1:30 pm - 4:00 pmFree Time
4:00 pm - 6:00 pmPoster Session
6:00 pmDinner
7:30 pm - 9:30 pmPostsynaptic Phenotypes: Signaling Pathways and Translation
Abnormalities in the regulation of activity-dependent translation were first identified in fragile X, but have since been recognized in many genetically determined forms of autism. This well-validated phenotype may represent a final common pathway linking many neurodevelopmental disorders.
Discussion Leader: Eric Klann (New York University, USA)
7:30 pm - 8:00 pmJoel Richter (University of Massachusetts Medical School, USA)
"Ribosome Profiling and Fragile X"
8:00 pm - 8:10 pmDiscussion
8:10 pm - 8:40 pmNahum Sonenberg (McGill University, Canada)
"Impact of Metformin on FXS Mice"
8:40 pm - 8:50 pmDiscussion
8:50 pm - 9:20 pmEmily Osterweil (University of Edinburgh, United Kingdom)
"Rebalancing Proteostasis in Fragile X"
9:20 pm - 9:30 pmDiscussion
Tuesday
7:30 am - 8:30 amBreakfast
8:30 amGroup Photo
9:00 am - 12:30 pmOther Disease Mechanisms: Presynaptic Phenotypes and Channelopathies
Recent findings suggest that FMRP does more than regulate dendritic protein synthesis. It also regulates presynaptic excitability via direct protein-protein interactions. In many cases, sporadic mutations in these same pathways have been found to cause ASDs.
Discussion Leader: David Nelson (Baylor College of Medicine, USA)
9:00 am - 9:30 amVitaly Klyachko (Washington University in St. Louis, USA)
"Channelopathy and Abnormal Excitability in Fragile X Syndrome: A New Role for mGluR5"
9:30 am - 9:40 amDiscussion
9:40 am - 10:10 amLeonard Kaczmarek (Yale University, USA)
"Slack Channels and Protein Translation"
10:10 am - 10:20 amDiscussion
10:20 am - 10:45 amCoffee Break
10:45 am - 11:10 amCarlos Portera-Cailliau (David Geffen School of Medicine at UCLA, USA)
"Network Defects Underlying Abnormal Sensory Perception in Fmr1 Knockout Mice"
11:10 am - 11:20 amDiscussion
11:20 am - 11:45 amHerve Moine (Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), France)
"Is Fragile X Syndrome a Lipidopathy?"
11:45 am - 11:55 amDiscussion
11:55 am - 12:20 pmClaudia Bagni (University of Rome Tor Vergata, Italy / University of Lausanne, Switzerland)
"From Molecules to Behavior: Disentangling FXS and ASD"
12:20 pm - 12:30 pmDiscussion
12:30 pmLunch
1:30 pm - 4:00 pmFree Time
4:00 pm - 6:00 pmPoster Session
6:00 pmDinner
7:30 pm - 9:30 pmOther Disease Mechanisms: Glial and Extracellular Phenotypes
FMRP also appears to regulate extracellular and retrograde signaling, and fragile X results in glial abnormalities which contribute to the overall clinical phenotype. These are additional areas of overlap with ASDs, and potential areas for therapeutic development.
Discussion Leader: Peter Todd (University of Michigan, USA)
7:30 pm - 8:00 pmIryna Ethell (University of California, Riverside, USA)
"The Role of MMP9 in Pathophysiology of FXS"
8:00 pm - 8:10 pmDiscussion
8:10 pm - 8:40 pmLaurie Doering (McMaster University, Canada)
"Astrocyte Modulation in Fragile X"
8:40 pm - 8:50 pmDiscussion
8:50 pm - 9:20 pmYongjie Yang (Tufts University, USA)
"Astroglial Glutamate Transporter Dysfunction in Fragile X"
9:20 pm - 9:30 pmDiscussion
Wednesday
7:30 am - 8:30 amBreakfast
9:00 am - 12:30 pmCircuits and Development
Abnormalities in neural circuits and their development over the lifespan add new dimensions to the complexity of fragile X and genetically-determined ASDs.
Discussion Leader: Kimberly Huber (University of Texas Southwestern Medical Center, USA)
9:00 am - 9:25 amSean McBride (Rowan University School of Osteopathic Medicine, USA)
"The Convergence of Circuitry and Genetic Dissection Uncovers Insulin Dysregulation in FXS"
9:25 am - 9:35 amDiscussion
9:35 am - 10:00 amAnis Contractor (Northwestern University, USA)
"Disrupted GABA Signaling During Cortical Development in Fragile X Syndrome"
10:00 am - 10:10 amDiscussion
10:10 am - 10:35 amCoffee Break
10:35 am - 11:00 amBryan Luikart (Geisel School of Medicine at Dartmouth, USA)
"Exploring the Neurophysiological Basis of Autism Using Genetic Pten Models"
11:00 am - 11:10 amDiscussion
11:10 am - 11:40 amPeter Kind (University of Edinburgh, United Kingdom)
"Rat Models of Fragile X and ASDs"
11:40 am - 11:50 amDiscussion
11:50 am - 12:20 pmDaniel Alkon (Neurotrope BioScience, USA)
"Modulation of PKC Epsilon as a Therapeutic Strategy"
12:20 pm - 12:30 pmDiscussion
12:30 pmLunch
1:30 pm - 4:00 pmFree Time
4:00 pm - 6:00 pmPoster Session
6:00 pmDinner
7:00 pm - 7:30 pmBusiness Meeting
Nominations for the Next Vice Chair; Fill in Conference Evaluation Forms; Discuss Future Site and Scheduling Preferences; Election of the Next Vice Chair
7:30 pm - 9:30 pmClinical Trials
Presentation of recent clinical trial results in subjects with fragile X and ASDs will be featured, along with discussion of trial methodology and lessons learned from previous efforts.
Discussion Leader: Laura Mamounas (National Institute of Neurological Disorders and Stroke, NIH, USA)
7:30 pm - 8:00 pmMustafa Sahin (Boston Children's Hospital, USA)
"Preclinical and Clinical Trials in Tuberous Sclerosis"
8:00 pm - 8:10 pmDiscussion
8:10 pm - 8:40 pmElizabeth Berry-Kravis (Rush University Medical Center, USA)
"Clinical Trials in Fragile X"
8:40 pm - 8:50 pmDiscussion
8:50 pm - 9:20 pmAlexander Kolevzon (Icahn School of Medicine at Mount Sinai, USA)
"Developing Novel Therapeutics in Neurodevelopmental Disorders: Challenges for Clinical Trial Readiness"
9:20 pm - 9:30 pmDiscussion
Thursday
7:30 am - 8:30 amBreakfast
9:00 am - 12:30 pmClinical Trials, Imaging, and Clinical Assessments
Quantification of human phenotypes by a variety of methods will be examined in this session, as well as additional results of clinical trials.
Discussion Leader: Elizabeth Berry-Kravis (Rush University Medical Center, USA)
9:00 am - 9:30 amFrank Kooy (University of Antwerp, Belgium)
"A Double Blind Crossover Trial of Ganaxolone in Patients with Fragile X Syndrome"
9:30 am - 9:40 amDiscussion
9:40 am - 10:10 amAditi Bhattacharya (Center for Brain Development and Repair, inStem, NCBS, India)
"Blood-Based Biomarkers for FXS: A Journey from Mouse Brain to Human Blood"
10:10 am - 10:20 amDiscussion
10:20 am - 10:45 amCoffee Break
10:45 am - 11:15 amJohn Sweeney (University of Texas Southwestern Medical Center, USA)
"Translational Neurophysiological Biomarkers in FXS"
11:15 am - 11:25 amDiscussion
11:25 am - 11:55 amJoseph Piven (University of North Carolina at Chapel Hill, USA)
"Infant Brain and Behavior Development in Autism and Fragile X"
11:55 am - 12:05 pmDiscussion
12:05 pm - 12:25 pmGordon Wang (Stanford University, USA)
"The Interplay of Synapse Diversity, Fragile X Syndrome and Drug Treatment"
12:25 pm - 12:30 pmDiscussion
12:30 pmLunch
1:30 pm - 4:00 pmFree Time
4:00 pm - 6:00 pmPoster Session
6:00 pmDinner
7:30 pm - 9:30 pmFuture Directions: Emerging Therapeutic Technologies
New techniques for gene editing and reactivation offer promise for a wide array of genetic diseases. At the same time, new proteomic discoveries offer the potential for blood-based biomarkers and enhanced clinical testing in ASDs.
Discussion Leader: Peter Kind (University of Edinburgh, United Kingdom)
7:30 pm - 8:00 pmGary Bassell (Emory University School of Medicine, USA)
"Cellular FXS Phenotypes in hiPSC Derived Neurons"
8:00 pm - 8:10 pmDiscussion
8:10 pm - 8:40 pmEric Klann (New York University, USA)
"Resetting Translational Homeostasis in FXS"
8:40 pm - 8:50 pmDiscussion
8:50 pm - 9:20 pmXinyu Zhao (University of Wisconsin-Madison, USA)
"New Strategies for Treating Fragile X: Getting to the Root of the Problem"
9:20 pm - 9:30 pmDiscussion
Friday
7:30 am - 8:30 amBreakfast
9:00 amDeparture

Funding for this conference was made possible (in part) by 1R13 HD088062-01 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). The views expressed in written conference materials or publications and by speakers and moderators do not necessarily reflect the official policies of the Department of Health and Human Services; nor does mention of trade names, commercial practices, or organizations imply endorsement by the U.S. Government.
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