C.2.1. 2001 Banbury Conference
The highly productive discussions focused attention on the role of FMRP as a mRNA
binding protein and upon the likelihood that the phenotype of FXS reflects where and if
the mRNAs that FMRP are translated within the neuron (or other cell). Of particular
interest were the first reports, independently discovered by Herve Moine and Jennifer
Darnell, of a motif in mRNA to which FMRP binds and the first report of a number of
mRNAs that appear to be associated with FMRP by co-precipitation. (All of these
findings have subsequently been published.) The conference focused interest on the
function of FMRP at a molecular level and at the level of the cell.
Robert Darnell’s introduction highlighted the uniqueness of fragile X. Loss of function
of one protein leads to an intriguing clinical syndrome, suggesting fragile X as an
important system for identifying RNA targets -- many of which may be candidate genes
for other neuropsychiatric disorders, understanding protein action on the targets, and
understanding RNA metabolism in neurons. The involvement of FMRP in regulation
activity-dependent protein synthesis strongly suggests a key role in learning and memory.
The initial session of the conference covered FMRP’s role in regulating RNA and
protein metabolism. Stephanie
Ceman proposed a model of FMRP regulation in which FMRP enters the nucleus, there
binds to mRNAs, is then phosphorylated, stopping any further RNA binding, and
transports its bound mRNAs elsewhere in the cells. This model helps to explain the
regulation of the varied and sometimes contradictory functions which have been
proposed for FRMP; the study of alternative phosphorylation states of FMRP is difficult,
requiring specific antibodies which have only recently become available. Ben Oostra
described his model of FMRP transport using PC12 cells with an inducible Tet-on system
fused with FMR1 and GFP. He concluded that FMRP can be transported from the
perikaryon via neurites to growth cones; the movement is microtubule-dependent and
occurs at a fast transport rate, similar to RNA transport. Yue Feng showed that absence
of FMRP may cause developmental abnormalities by defective regulation of glial cell
proteins, including MPB, opening up the question of whether FMRP has distinct roles in
neurons and glial cells. Kirk Jensen discussed the roles of RNA binding proteins in
neurons, focusing on how Nova regulates alternative splicing of several neuronal
mRNAs; FMRP itself exists in several isoforms, with little evidence thus far of
differential functions of these isoforms. Harry Orr discussed spinocerebellar ataxia type
1 (SCA1), demonstrating that trinucleotide expansion in the ataxin 1 protein leads to
over/under expression of ten mRNAs and interferes with RNA transport. Doug Black
described neuronal regulation of pre-mRNA splicing, demonstrating that stimulation of
neurons can feed back to affect splicing of mRNAs; this may suggest a neuronal
mechanism for regulating expression of different isoforms of FMRP.
The second session focused on RNA targets of FMRP. Jennifer Darnell discussed her
methods for identifying specific targets of the RGG box and KH domains of FMRP,
including several which are phenotypically relevant to fragile X syndrome. She has
identified a 3 dimensional RNA structure called a G-quartet which appears to predict
binding to FMRP. William Greenough discussed possible phenotype contributions of
some FMRP-interacting mRNAs, especially regulation of glucocorticoid receptor
expression. Herve Moine further described the detailed physical interaction of FMRP
with RNAs containing G-quartets, and Lynne Regan presented data on the role of
FMRP’s KH domains in recognizing RNAs. These detailed descriptions of FMRPmRNA interactions have shed new light on the mechanism of the increased phenotypic
severity of the I304 point mutation previously described by the Belgian-Dutch
Collaborative group.
The next session covered the involvement of FMRP in RNA trafficking and
translational control. Oswald Steward discussed targeting of mRNA to synaptic sites on
dendrites; Gary Bassell talked about regulation and function of FMRP and FMR1 mRNA
trafficking in developing neurons. Mathias Hentze described translational regulation by
mRNA binding proteins, many of which are now known to form protein complexes with
FMRP. Joel Richter described CPEB-mediated translational control and how this may
interact with the FMRP-RNP complex. Finally, Justin Fallon discussed regulation of
FMR1 mRNA translation in neurons.
In the fourth session, drosophila models of fragile X were described. Tom Jongens
analyzed behavior of dFXR mutant drosophila, demonstrating that the flies have
abnormal circadian rhythms and courtship rituals, and noted morphological abnormalities
in neurons. These are likely fly homologs of hyperarousal and social anxiety in humans
with fragile X, and may serve as a useful behavioral assay for potential therapeutic
interventions. Alexandre Costa presented studies of dFXR-Orb interactions and mRNA
localization/translation; the 2 proteins interact extensively during drosophila development
and appear to regulate transport and translation of a subset of mRNA’s. Joanella Morales
described how dFXR regulates brain morphology and function in the CNS; null mutant
flies displayed distinctly abnormal neuronal morphology which was somewhat different
from the abnormalities previously described in the neuromuscular junction. She
discussed the role of futsch as well, and how these findings could be reconciled with
those of Broadie et al. Heinrich Matthies (from the Broadie group) showed evidence that
dFXR acts as a translational suppressor of futsch to control microtubule dynamics
underlying synaptic structure and function. Kevin Moses presented a genetic screen for
dominant modifiers of DFXRP/ Jean-Louis Mandel presented data on FMRP interactors.
The final session of the meeting focused on physiology. Kimberly Huber demonstrated
a role for ERK in mGluR and protein-synthesis dependent LTD. Mark Bear presented
evidence that mGluR-mediated LTD is excessive in the FMR1 knockout mouse.
Roberto Malinow described AMPA receptor trafficking during synaptic plasticity. Karen
Zito described studies identifying genes differentially expressed in wildtype and FMR1
knockout mouse barrel cortex. Robert Darnell summed up the meeting and a general
discussion followed.
Comments from participants, 2001 Conference
Gary Bassell reported that his collaborative work with Jennifer and Robert Darnell to
identify domains on FMRP necessary for activity-dependent regulation arose the last two
Banbury meetings and that one of his former grad students is now a postdoctoral fellow
with Bob Darnell. Gary commented: “This remains my favorite meeting each year.
There are many groups of investigators from different disciplines i.e. Neuroscience,
Biochemistry, Cell Biology and Genetics- people that you don't see all year at specialized
society meetings. Another strength of the meeting is the collegial atmosphere with much
time for lively discussion about research in Fragile X.”
Laura Antar added “Once again, the Banbury has been the highlight of my year. I learn
more at the Banbury than at any other meeting-- partly because of the tight focus, partly
because of the high quality of investigators present, and partly because of the small
number of participants.”
Jennifer Darnell reported that “following the last meeting we began working with Jerry
Yin and started a new collaborative project with Steph Ceman in S. Warren's lab. So
these two collaborations definitely arose from the 2002 meeting. I find these small, very
specialized meetings to be the most valuable in terms of information exchange and
establishing or renewing collaborations. I also feel that they are a great venue for
exchanging data that's really fresh and novel.”
Steve Warren reported “The Banbury meetings on fragile X syndrome have always
been the yearly highlight as meetings on this subject go. Every year it gets better and last
year was the best. The invited speakers are better picked from year to year with stronger
and stronger scientists attending. It is particularly good that the invited attendees are a
good mix of long standing fragile X investigators, those junior and new to the field and
leading investigators not currently working on fragile X. This latter group is always
interesting to follow a year after the meeting when one finds many of them are now doing
fragile X research.
David Nelson said that he’d been attending fragile X meetings for over 15 years and
the 2001 Banbury meeting was the best one he'd ever experienced.
C. 2.2. 2002 Banbury Conference
Robert Darnell’s introduction highlit the uniqueness of fragile X. Loss of function of one
protein leads to an intriguing clinical syndrome, suggesting fragile X as an important
system for identifying RNA targets---many of which may be candidate genes for other
neuropsychiatric disorders, understanding protein action on the targets, and
understanding RNA metabolism in neurons. The involvement of FMRP in regulation
activity-dependent protein synthesis strongly suggests a key role in learning and memory.
The initial session of the conference covered FMRP’s role in regulating RNA and protein
metabolism. Stephanie Ceman proposed a model of FMRP regulation in which fmrp
enters the nucleus, there binds to mRNAs, is then phosphorylated, stopping any further
RNA binding, and transports its bound mRNAs elsewhere in the cells. This model helps
to explain the regulation of the varied and sometimes contradictory functions which have
been proposed for FRMP; the study of alternative phosphorylation states of FMRP is
difficult, requiring specific antibodies which have only recently become available. Ben
Oostra described his model of FMRP transport using PC12 cells with an inducible Tet-on
system fused with FMR1 and GFP. He concluded that FMRP can be transported from
the perikaryon via neurites to growth cones; the movement is microtubule-dependent and
occurs at a fast transport rate, similar to RNA transport. Yue Feng showed that absence
of FMRP may cause developmental abnormalities by defective regulation of glial cell
proteins, including MPB, opening up the question of whether FMRP has distinct roles in
neurons and glial cells. Kirk Jensen discussed the roles of RNA binding proteins in
neurons, focusing on how Nova regulates alternative splicing of several neuronal
mRNAs; FMRP itself exists in several isoforms, with little evidence thus far of
differential functions of these isoforms. Harry Orr discussed spinocerebellar ataxia type
1 (SCA1), demonstrating that trinucleotide expansion in the ataxin 1 protein leads to
over/under expression of ten mRNAs and interferes with RNA transport. Doug Black
described neuronal regulation of pre-mRNA splicing, demonstrating that stimulation of
neurons can feed back to affect splicing of mRNAs; this may suggest a neuronal
mechanism for regulating expression of different isoforms of FMRP.
The second session focused on RNA targets of FMRP. Jennifer Darnell discussed her
methods for identifying specific targets of the RGG box and KH domains of FMRP,
including several which are phenotypically relevant to fragile X syndrome. She has
identified a 3 dimensional RNA structure called a G-quartet which appears to predict
binding to FMRP. William Greenough discussed possible phenotype contributions of
some FMRP-interacting mRNAs, especially regulation of glucocorticoid receptor
expression. Herve Moine further described the detailed physical interaction of FMRP
with RNAs containing G-quartets, and Lynne Regan presented data on the role of
FMRP’s KH domains in recognizing RNAs. These detailed descriptions of FMRPmRNA interactions have shed new light on the mechanism of the increased phenotypic
severity of the I304 point mutation previously described by the Belgian-Dutch
Collaborative group.
The next session covered the involvement of FMRP in RNA trafficking and translational
control. Oswald Steward discussed targeting of mRNA to synaptic sites on dendrites;
Gary Bassell talked about regulation and function of FMRP and FMR1 mRNA
trafficking in developing neurons. Mathias Hentze described translational regulation by
mRNA binding proteins, many of which are now known to form protein complexes with
FMRP. Joel Richter described CPEB-mediated translational control and how this may
interact with the FMRP-RNP complex. Finally, Justin Fallon discussed regulation of
FMR1 mRNA translation in neurons.
In the fourth session, drosophila models of fragile X were described. Tom Jongens
analyzed behavior of dFXR mutant drosophila, demonstrating that the flies have
abnormal circadian rhythms and courtship rituals, and noted morphological abnormalities
in neurons. These are likely fly homologs of hyperarousal and social anxiety in humans
with fragile X, and may serve as a useful behavioral assay for potential therapeutic
interventions. Alexandre Costa presented studies of dFXR-Orb interactions and mRNA
localization/translation; the 2 proteins interact extensively during drosophila development
and appear to regulate transport and translation of a subset of mRNA’s. Joanella Morales
described how dFXR regulates brain morphology and function in the CNS; null mutant
flies displayed distinctly abnormal neuronal morphology which was somewhat different
from the abnormalities previously described in the neuromuscular junction. She
discussed the role of futsch as well, and how these findings could be reconciled with
those of Broadie et al. Heinrich Matthies (from the Broadie group) showed evidence that
dFXR acts as a translational suppressor of futsch to control microtubule dynamics
underlying synaptic structure and function. Kevin Moses presented a genetic screen for
dominant modifiers of DFXRP/ Jean-Louis Mandel presented data on FMRP interactors.
The final session of the meeting focused on physiology. Kimberly Huber demonstrated a
role for ERK in mGluR and protein-synthesis dependent LTD. Mark Bear presented
evidence that mGluR-mediated LTD is excessive in the FMR1 knockout mouse. Roberto
Malinow described APMA receptor trafficking during synaptic plasticity. Karen Zito
described studies identifying genes differentially expressed in wildtype and FMR1
knockout mouse barrel cortex. Robert Darnell summed up the meeting and a general
discussion followed.
C. 2. 3. 2003 Banbury Conference
This meeting, organized by Mark Bear and Michael Tranfaglia, focused on synaptic
function in fragile X syndrome. Emerging data suggest that aspects of Fragile X
syndrome reflect synaptic dysfunction, specifically, weaker excitatory synapses,
increased numbers of long thin dendritic spines, increased susceptibility to network
seizure activity. One suspected function of the fragile X mental retardation protein
(FMRP) is regulation of protein synthesis at synapses, and one synaptic trigger for
protein synthesis is activation of group 1 metabotropic glutamate receptors (mGluRs).
Some documented consequences of mGluR-dependent protein synthesis are long-term'
synaptic depression (LTD), elongated dendritic spines, and epileptiform activity. This
meeting explored the possibility that aspects of Fragile X syndrome could reflect
exaggerated mGluR function occurring in the absence of FMRP as well as broader issues
surrounding dendritic protein synthesis and structural plasticity in Fragile X.
In the introductory session, Katherine Clapp and Michael Tranfaglia provided an
overview of the Fragile X mutation, the consequences in humans, and treatment strategies
tried to date. Mark Bear gave an overview of synaptic transmission and plasticity, and the
mGluR hypothesis of Fragile X.
The first session focused on dendritic RNA, activity-dependent protein synthesis, and
structural plasticity. Jerry Yin discussed how active synapses are "tagged" by activity to
generate synapse-specific changes in protein synthesis and how this mechanism may go
awry in fragile X; prevailing theories of synaptic tagging correlate closely with recent
findings of mechanisms of normal function of dFXRP in drosophila. Laura Antar
described how mRNA is transported from nucleus to synapse, and how this trafficking is
regulated in conjunction with FMRP in response to synaptic activity. Oswald Steward
described the targeting of mRNA to synaptic sites on dendrites and mechanisms of LTD.
Justin Fallon discussed translational regulation of the Fragile X message, and how FMRP
may be involved in regulation of translation of a discrete subset of dendritic mRNAs.
Ivan Jeanne Weiler presented data on activity-dependent regulation of synaptic mRNA
translation. Peter Vanderklish described relationships between dendritic translation and
synaptic structure, focusing on IRES dependent translation and LTP; he has demonstrated
that agonism of group I mGluR’s can induce the long, thin dendritic spines which are
characteristic of fragile X and other developmental disorders. Bill Greenough outlined
structural consequences of the absence of FMRP, including apparent abnormalities in
dendritic pruning seen in examination of whisker barrels. Ben Oostra presented new data
on findings of cerebellar ataxia and inclusion bodies, both in premutation males and in
premutation male knockout mice. Finally, Edouard Khandjian presented data on a
xenopus model for fragile X, and the insights which this may offer in understanding the
transport functions of FMRP.
The next session focused on the metabotropic glutamate receptors (mGluRs). Ever since
the original discovery by Bill Greenough’s group that mGluR activation triggers local
synthesis of FMRP, there has been an intriguing thread linking the biology of mGluRs,
synaptic protein synthesis regulation, and Fragile X. Robert Wong presented one recently
characterized consequence of mGluR-dependent protein synthesis, the induction and
maintenance of epileptiform activity in the hippocampus. He showed data indicating
abnormal epileptiform activity in FMR1 knockout mice as compared to wildtype,
correlating with the human phenotype of seizure disorder. Robert Bauchwitz then
discussed one of the more robust phenotypes in the Fmrl knockout mouse, audiogenic
seizure, and presented data showing that administration of the mGluR5 antagonists
MPEP rescues this phenotype. Finally, an extensive discussion of mGluR behavioral
pharmacology was presented by Will Spooren, with particular emphasis on the anxiolytic
effects of mGluR5 antagonists; a discussion of medicinal chemistry and
pharmacokinetics of mGlur5 antagonists was presented by Fabrizio Gasparini, one of the
pioneers in this field.
Next followed a session on AMPA receptor regulation at the synapse. Synaptic
expression of AMPARs is regulated by activity and is believed to be the basis for
synaptic plasticity that is important for refining cortical circuits during development and
storing information in adults. Robert Malinow began by discussing the molecular basis of
AMPA receptor regulation during bidirectional synaptic plasticity. Kim Huber discussed
the effect of the loss of synaptic AMPARs that accompanies induction of two forms of
LTD in the hippocampus, one that is mGluR and protein-synthesis dependent, and the
other that is not. David Linden described the role of mGluRs (primarily mGluR1) and
protein synthesis in regulation of AMPARs that accompanies LTD in the cerebellum.
Peter Carlen presented biochemical data suggesting reduced AMPAR expression in the
cortex of the FMRl knockout mouse. John Larson described a role for AMPAR
regulation in olfactory learning, and his development of an olfactory descrimination assay
of cognitive function in the fmr1 knockout mouse. Finally, Elizabeth Berry-Kravis
discussed her ongoing phase II clinical trial of a drug, Ampakine CX516, that enhances
AMPAR function for the treatment of Fragile X syndrome.
The final session brought together new information about the biology of FMRP,
beginning with a talk by Steve Warren on microarray studies of gene expression in fragile
X, highlighting potentially significant targets of FMRP which could affect CNS function,
and on new findings on the fragile X permutation syndrome. Jennifer Darnell presented
evidence of recognition sequences which determine FMRP binding and, presumably,
regulation. Andrea Beckel-Mitchener discussed specific target mRNAs identified by her
group, and their potential function, with particular focus on decreases in levels of the
glucocorticoid receptor found in the KO mouse. Daniella Zarnescu presented new data on
modifiers of drosophila and their potential significance for our understanding of the
human disease; she focused on one modifier, Penelope, which is a known cancer
suppressor gene. Amy Caudy described new findings of RNA interference and its
possible role in the pathophysiology of fragile X. Finally, David Nelson summarized a
broad range of studies in his research group which focus on identifying the basic
functions of FMRP and describing a behavioral phenotype of the knockout mouse.
Convergent technologies in molecular, cell, and neurobiology have resulted in significant
new insights into fragile X. This meeting concluded with a discussion of the prospects for
developing new and effective treatments for the disorder and specific steps which might
now be taken to facilitate the process.
C. 2.4. 2004 Banbury Conference
In April 2004, the 5th annual Fragile X research meeting was held at the Banbury Center.
This year’s focus was pharmacological treatments for Fragile X: which existing drugs
and experimental new compounds might be further evaluated for treating Fragile X
syndrome. The participants were roughly equally drawn from the pharmaceutical
industry, representing seven different companies including Novartis, Addex, Lilly,
Merck, and Hoffman LaRoche, and the university-based basic research community. The
previous meetings in this series have focused on basic research describing the behavioral,
molecular, morphological and pharmacological characteristics of human fragile X
syndrome and its animal models. The 2004 meeting focused upon putting this basic
knowledge to use to address translational questions: What would be necessary to go from
the basic research, including that emanating from study of human clinical syndromes
with similar symptoms, to the development and assessment of pharmacological
treatments for fragile X syndrome? To help in both planning and running the meeting,
we recruited Dr. Will Spooren, a drug development scientist of Hoffman LaRoche
(Project Leader, F. Hoffmann-La Roche, Pharma Research Basel Discovery –
Neuroscience, Psychiatry Disease Area), who served as conference co-chair with PI
William Greenough. Dr. Spooren, in turn, recruited key researchers from the
pharmaceutical industry with specializations in drug development, receptor systems and
psychiatric aspects of a range of drug classes. The meeting had a "cut to the chase"
treatment development orientation and thus focused on drugs and drug classes which
show promise as potential treatments for fragile X.
Much discussion centered on receptor/ transmitter systems that current research indicates
are impaired or otherwise implicated in fragile X syndrome, particularly those involving
glutamate and GABA, and compounds that target those systems. By the end of the
meeting, it had become clear that more work is needed to design good clinical trials to
effectively test drug treatments for fragile X. Several exciting new collaborations
between industry and university scientists were established at the meeting, and several
drug trials in Fragile X patients are now being planned.
In the introductory session, chaired by Dr. Elizabeth Berry-Kravis, a parent perspective
of the fragile X syndrome was provided by Katherine Clapp of FRAXA Research
Foundation, in an effort to familiarize scientists new to the field with the clinical
presentation of fragile X. This was followed by an overview of phenotype and of
patterns of medication use by Don Bailey of the University of North Carolina, Chapel
Hill. His group has conducted the longest longitudinal studies of fragile X children, and
has systematically examined the prevalence of autism and autistic symptoms in fragile X
children.
Dr. Randi Hagerman from the M.I.N.D. Institute at the University of California, Davis
discussed psychopharmacological interventions in fragile X, with an emphasis on types
of behavioral problems encountered in the pediatric clinic. A review of the few clinical
trials done to date in fragile X was included. This was followed by Stephen T. Warren of
Emory University who described molecular mechanisms of the fragile X phenotypes; his
research group is studying several model systems, including mice and drosophila, and
has developed phenotypes which may be useful for testing putative therapeutic agents.
The second session focused on the technology of mouse models, both for fragile X in
particular, and for neuropsychiatric disorders in general. Representing pharmaceutical
industry research, Thomas Steckler of Johnson & Johnson discussed pitfalls of attempting
to model complex human conditions like depression and anxiety in mice, and his
development team’s experience with CRF antagonists. Just as depression and anxiety are
typically stress-related disorders, fragile X has also been reported to involve exaggerated
cortisol responses to stress. This implies that agents like CRF antagonists, which may
modulate the HPA axis, may have applications in the treatment of fragile X. The next
presentation, by Richard E. Paylor of Baylor College of Medicine, dealt with the
behavioral phenotype of fmr1 KO mice and the role of genetic background; a behavioral
phenotype has been surprisingly difficult to obtain in the KO mouse, and many of the
differences found to date have been highly strain-dependent. This has made evaluation of
potential pharmacologic treatments especially difficult.
Ben A. Oostra of Erasmus Universiteit, Rotterdam then presented evidence of enhanced
LTD at enlarged Purkinje cell spines in the cerebellum, which causes motor learning
deficits in fmr1 KO mice. This phenotype manifests as aberrant eye-blink conditioning,
an assay which can also be utilized in human subjects as a potential outcome measure for
clinical trials of investigational agents. Miklos Toth of Cornell University Medical
College then discussed his studies of the hyperactivity of fragile X mice to sensory
stimuli, as evidenced by increased startle response and increased sensitivity to audiogenic
seizures. He is using pharmacologic probes to elucidate causes of network
hyperexcitability and alterations in FMRP-target expression.
The third session focused on functional consequences of the fragile X mutation in the
nervous system. Robert Wong of SUNY Downstate discussed the role of metabotropic
glutamate receptors in epileptogenesis in fragile X syndrome. He has found that neural
circuits in fmr1 KO mouse hippocampal slices show markedly increased epileptogenesis
compared to normal littermates, that this increase is mediated by mGluR5, and that this
aspect of neurophysiology can be normalized by administration of the mGluR5
antagonist MPEP. Addressing a similar question in intact mice, Robert P. Bauchwitz of
Columbia University described enhanced susceptibility to audiogenic seizure in all strains
of KO mice examined, but with significant variability depending of genetic background.
In all strains, audiogenic seizure could be prevented by administration of MPEP, but with
wide variation in ED50.
Peter W. Vanderklish of Scripps Research Institute then presented his findings on
regulatory interactions between synaptic structure and local translation. He has
demonstrated that activation of group I mGluRs can induce long, thin dendritic spines
over short time periods---morphology reminiscent of that seen in fragile X; he has been
investigating the specific events in translational regulation at the dendrite which control
this process, and how they may be altered in fragile X. He was followed by Eric Klann
of Baylor College of Medicine, discussing regulation of translation signaling pathways
during mGlur-LTD in fmr1 knockout mice. He has quantified many elements of the
mGluR signaling pathways and shown how these respond to synaptic activity in normal
and fmr1 KO mice. J. Julius Zhu, from the University of Virginia School of Medicine,
then presented on Ras signaling of excitatory synapses of FMR1 knockout mice; precise
alterations in elements of signaling pathways in fragile X have been described in his
work, offering potential targets for drug discovery. Finally Mark Bear, of MIT, described
his original findings of enhanced mGluR-LTD in the fmr1 KO mouse, then elaborated by
discussing mechanisms in various brain regions which could explain other aspects of the
fragile X phenotype.
Session 4 was chaired by two representatives of the pharmaceutical industry, Will
Spooren of Hoffmann-LaRoche and Graeme Bilbe, Global Head of Neuroscience
Research for Novartis. This session highlighted possible “drugable” targets in fragile X,
and explored paths to development of viable treatment strategies. Michael R. Tranfaglia
MD, Medical Director of FRAXA Research Foundation, outlined the use of available
medications in the treatment of fragile X. Graeme Bilbe then presented an overview of
the drug discovery process, with an emphasis on specific needs of the fragile X field,
followed by presentations addressing specific neurotransmitter systems. Vincent Mutel
of Addex Pharmaceuticals discussed development of positive and negative allosteric
modulators of mGluR’s, and their potential uses in psychiatry. Michael P. Johnson of Eli
Lilly discussed his experiences in development of mGluR2/3 agonists for treatment of
anxiety, and their potential application to treatment of fragile X and related disorders.
Fabrizio Gasparini of Novartis then presented “Allosteric Modulation for the mGlu
Receptors: Antagonists, Positive Modulators, Neutral Ligands” which included a brief
history of the search for specific mGluR5 antagonists.
The series of presentations continued with Will Spooren discussing Neurokinin 3 (NK3)
receptors as a new target for the treatment of psychosis. Gerard R. Dawson of Merck
presented on the role of GABA-A receptor subtypes in anxiety and cognition. Bernhard
Bettler of Universitat Basel discussed GABA-B receptors as therapeutic targets for CNS
disorders, and Carl Dobkin, New York State Institute for Basic Research, presented his
findings of seizure susceptibility of the fragile X mouse and alterations of the
GABAergic system. To conclude the day, a lengthy discussion involving the fragile X
experts and the pharmaceutical researchers highlighted potentially fruitful areas for future
exploration, and spawned several collaborations to investigate specific neurotransmitter
systems in fragile X.
Session 5 had a distinct clinical/therapeutic focus. Thomas Jongens of U. Penn presented
evidence of a robust cognitive and behavioral phenotype in dFXR null mutant
drosophila; he further described rescue of the phenotype using the mGluR5 antagonist
MPEP and lithium, which inhibits several elements of the mGluR signaling pathways.
Peng Jin of Emory also noted a distinct phenotype in drosophila, but one of reduced
survival of dFXR null mutants on a common kind of laboratory fly food. Even though
this phenotype is not obviously neural, it is nevertheless rescued by administration of
MPEP, and may serve as the basis for a higher throughput drug screen. Herman
Westenberg of Utrecht University then presented findings from studies of the role of
dopamine in anxiety disorders, especially OCD and social phobia. These disorders are
highly relevant to the clinical presentation of fragile X, and may warrant investigation of
dopaminergic systems. Elizabeth Berry-Kravis concluded the formal presentations with a
description of her ongoing trial of CX516, a compound that facilitates AMPA receptor
transmission.
The final session was an open discussion moderated by Michael Tranfaglia of FRAXA
and Will Spooren, with the express purpose of defining strategies to develop treatments
for fragile X. The expertise of pharmaceutical industry scientists combined with the
experience of fragile X researchers to generate a list of important interim goals, such as
devising improved outcome measures to assess efficacy in fragile X clinical trials.
Summary: Convergent technologies in molecular, cell, and neurobiology have resulted in
significant new insights into fragile X. At least some existing drugs may be ready for
preliminary evaluation in fragile X syndrome and animal models of it. This meeting
concluded with a discussion of the prospects for developing new and effective treatments
for the disorder and specific steps which might now be taken to facilitate the process. One
point of agreement was the importance of clear, ideally quantifiable descriptions of the
phenotype of the syndrome for use in evaluating the efficacy of drug treatments. It was
decided that this would be one of the topics of the next meeting.