Research Progress in
Fragile X Syndrome –
Brain Function to New
Ideas for Treatment
Elizabeth Berry-Kravis MD PhD
Rush University Medical Center, Chicago
Disclosures: EBK has received funding from Neuropharm LTD and
Seaside therapeutics to conduct clinical trials in FXS, and has served as
a consultant for Novartis Pharmaceuticals and Roche Pharmaceuticals
Fragile X Syndrome
• Form of X-linked MR/ID
discovered by Martin and
Bell 1943
• Lubs fragile site 1969
• 1991 – Caused by mutations
that inactivate FMR1 gene
• Prevalence – 1:4000 males
MOST COMMON
KNOWN INHERITED
and females
FORM OF
• Carriers – 1:100-250
COGNITIVE
females, 1:250-800 males
DISABILITY
• All ethnic groups worldwide
Features of Fragile X Syndrome
• Physical: large prominent ears, long
face, large head, prominent jaw and
forehead, midfacial hypoplasia,
hyperflexible joints, large testis
• Intellectual Disability or LD
• Behavior problems: anxiety,
hyperactivity, distractibility,
perseveration, aggression
• Seizures – 15%
• Strabismus – 30%
• Medical: otitis, sinus, MVP, reflux,
sleep apnea, loose stools, allergies
FXS Intellectual Disability
• Males - average adult IQ about 40
and mental age 5-6y, range severe
ID to normal (mosaics)
• IQ scores higher when young,
decline with age
• Specific cognitive profile
• Achievement and Adaptive skills
higher
Fragile X Syndrome
Characteristic cognitive pattern with
prominent executive function deficits
• Weaknesses
• Strengths
– Auditory processing
– Receptive vocabulary
– Sequencing
– Syntax
– Abstraction
– Imitation
– Short-term memory
– Grammatical
– Topic maintenance/
structure
"connectedness"
– Visual memory
– Mathematics
– Simultaneous
– Working memory
processing
– Coordination/praxis
– Experiential learning
Why is Math so hard in FXS?
FXS Developmental
Problems
• Motor delays in some
• Hypotonia - orofacial
when young
• Fine motor problems poor writing ability
• Gross motor
clumsiness
• Speech/language
delays
• Delayed imitative and
symbolic play
FXS Developmental Problems
• Parents most frequently become
concerned first about speech delay
• Other concerns that may lead to child’s
initial evaluation:
– Motor delay
– Extreme hypersenstivity/defensiveness
– Hyperactivity or anxiety
– Cognitive delays or LD at school age
• Therapists for child with delay often first
encourage testing – if parents don’t
recognize magnitude of problem or
doctors are discouraging testing
FXS Developmental Problems
• Most FXS patients can be identified with
delay on developmental screens by 9-18
months
• Average age of diagnosis still between
3-4 years – no change in past 10 years
(Bailey)
• Miss early intervention
• New NFXF/FXCRC goal: diagnosis
before age 2 – working on Pediatricians
FXS - Pattern of
Speech/Language Deficits
• Most abnormal
– Jargon/tangential
language
– “Jocular litanic
phraseology”
– Perseverative speech
– Lack of use of
gestures
– Talking to self
– Cluttering
• Less
abnormal
– Fluency
– Prosody
• Strengths
– Grammar
– Vocabulary
Language Characteristics in FXS
Relative to Normal Mental-Age
Matched Controls and
Developmentally Delayed Subjects
• Decreased intelligibility
– Vowels sounds more variable than normal
developmentally matched controls
– Poor oromotor control
– Faster rate of speech
• Decreased length of utterances
• Increased self-repetitious and
perseverative language
• Single word vocabulary a strength
Language in FXS vs Autism
• More impaired in non-verbal
communication than autistic group
• More impaired in expressive
language
• Less impaired in receptive language
which is a strength
• Tangential language more prevalent
than in autism or general
developmental delay (possibly due to
anxiety, inhibitory control deficits)
FXS Socialization
Deficits
Friendly but
social anxiety
• Good understanding of facial expression –
different from typical autism
• Deficits in peer entry
• Defcits in interpreting social cues – correlate
with anxiety, attention problems, social
problems
• Discrimination deficit - body language, hidden
curriculum
FXS - Female Affecteds
• More mildly involved
• Average IQ 80
• NVLD, VIQ>PIQ, poor math, very impaired
executive function, distractibiity
• Same cognitive pattern as males
• Physical features/medical problems
variably present
• Social/psychiatric disability common –
anxiety/shyness, oddness
• Decreased education, job stability,
socioeconomic status
FXS Treatment in
Clinic - Supportive
Rush FXS Clinic since
1992 > 400 patients
• Early intervention
• Intensive speech
therapy
• OT with sensory
integration
• Inclusion in school as
much as possible
• Educational curriculum,
environment, teaching
style matched to FXS
cognitive profile
• Socialization program
• Behavior plan
• Behavior medications
for ADD/anxiety
• Aggressive tx of otitis
– tubes/audiology
• Manage sleep apnea
• Yearly eye exams
• Control seizures
• Orthopedics if needed
• Monitor for MVP/heart
• Genetic counseling
• Discuss reproductive
options
Psychopharmacology in
Fragile X Syndrome
• Targets behavior to improve functioning
• Supportive, does not target underlying
cognitive problem
• Only one prior controlled trial in FXS (N=15)
shows Ritalin effective in 2/3 of boys
• Therapeutic decisions based on target
largest problem symptom complex(es) – trial
and error
• May need to treat multiple behavioral
domains
Decision to Use Behavioral
Medication
• Individual engaging in dangerous
behaviors
• Individual is dysfunctional from behavior
• Individual could accomplish more or be
higher functioning if specific behavior is
managed
– Increase ability to participate
– Able to be in more inclusive setting
• Not necessarily “when all else fails”
• ALWAYS an adjunct to behavioral,
environmental measures
FXS - Types of Medications and
Indications*
*meds may be targeting several clusters
Problem
Medication
Behavior Cluster Class
Medications
Distractibility/
Hyperactivity
Overarousal/
Hypersensitivity
Anxiety/OCD/
Perseverative
Mood Lability
Stimulants
Methylphenidate,
Adderall, Provigil
Alpha-agonists
Clonidine, Tenex
SSRIs
Prosac, Zoloft,
Celexa, Lexapro
Antidepressants,
AEDs, Lithium
Atypical
Antipsychotics,
Tricyclics, Effexor, Li,
SSRIs, VPA, TPX, CBZ
Aggression/Self
abusive
Risperdal, Abilify,
Seroquel, Geodon
Abilify (aripiprazole) – New Mechanism
• Partial agonist (activator) at dopamine D2 and
serotonin 5HT1a receptors, antagonist at
5HT2a
• May be particularly good in FXS because may
help with ADHD symptoms (dopamine effect)
as well as anxiety/irritability
• Likewise can get aggravation of irritability,
perseveration, agitation due to dopamine
effect in subgroup
• Social behaviors better in animal models
compared to other antipsychotics
• Thus far best antipsychotic response rate for
FXS – can give dramatic social improvements
Abilify – High Response Rate in
FXS (2004-2007)
Unknown
7%
Abilify Responce <18 (n=43)
Abilify Responce (n=64)
Failed
30%
Unknown
5%
Failed
30%
Successfully
Treated
63%
Abilify Responce >18 (n=21)
Successfully
Treated
65%
Failed
29%
Successfully
Treated
71%
Rush Fragile X Clinic:
Supportive Psychopharmacology
is Helpful in FXS…
Berry-Kravis and Sumis, 2006
…but treating
the underlying
disorder would
be better
208 trials
136 patients
Attention
Hyperactivity
52 trials
231 trials
100 trials
123 patients 58 patients 52 patients
Anxiety
Mood
Aggression
Irritability
Hyperarousal
Oversensitivity
FMR1: The Fragile X Gene
Normal X
Chromosome
Premutation
(small size
increase
in FMR1)
fragile X
chromosome
Full mutation
(large size
increase
in FMR1)
fragile X
chromosome
FMR1 mRNA
FMR1 gene
FMRP
12 - 50
CGG repeats
FMR1 mRNA
FMRP
FMR1 gene
50 - 200
CGG repeats
FMR1 gene blocked
(methylated)
CH3
CH3
200+
CGG repeats
fragile site
Simple DNA test to diagnose
FXS – measures repeat size
Carrier state passed through
many generations before FXS
No FMR1
mRNA
Neural dysfunction
Intellectual compromise
Fragile X Syndrome
No FMRP
FMRP Expression and Disability
100
Social anxiety/shyness
FMRP
Distractibility/hyperactivity
Executive deficits
Spatial perceptual deficits
NVLD
Intellectual Disability
0
Disability
The Fragile X Mouse
(Knockout; K/O)
• fmr1 gene inactivated
• No active FMRP
• Subtle cognitive
problems
• Audiogenic seizures
• Good neurobiological
model to answer
question: WHAT
DOES FMRP DO?
Both FXS Mouse
and Human
Brains:
Dendritic Spines
are Abnormal in
FXS with
Immature Long
Spines at Brian
Connections
FMRP regulates maturation of
brain synapses (connections)
McKinney et al, AJMG -B: Neuropsychiatric Genetics, 2005
FMRP in
Dendrites (Brain
Connections)
FMRP in RED in tip of
neural dendrites and
where processes are
forming
•Antar et al, J. Neurosci 2004
FMRP regulates proteins made at brain
connections (in dendrites) - proteins have to
be made in right amount for connection to
mature and work right.
How loss of protein regulation
causes weak connections in FXS
glu
LTD
glu
Excessive LTD – due to
mGluR system overactivity
AMPA
AMPA
AMPA
mGluR
AMPA
mGluR
FMRP
ribosome
ribosome
AMPA
AMPA
FMRP
Dendrite
Normal
Mature connection
mGluR Theory of Fragile X
Fragile X
Immature connection
(too weak)
New Research is Leading to
Future Treatments for Fragile X
• Specific glutamate (group I
mGluR) pathway regulated by
fragile X protein (FMRP) in
neurons
• Regulates strength of neural
connections needed for
learning
• Overactive when FMRP not
there – messes up
connections
• Can block pathway with new
drugs (mGluR blockers)
being developed
Normal
Fragile X
Drug
glu
AMPA
4
3
Other systems
AMPA
mGluR
1
X
X
2
ribosome
AMPA
Potential
Mechanisms
for New
Treatments
of FXS
AMPA
Excessive LTD – due to
mGluR system overactivity
Dendrite
Fragile X
Immature connection
(too weak)
Targeted Treatments we have tried
Ampakine
Excessive LTD
glu
Stronger connection
AMPA
glu
AMPA
mGluR
mGluR
ribosome
AMPA
AMPA
Activate
AMPA
receptors
Raise BDNF
– bring
AMPA
receptors to
synapse
Fragile X
Immature connection
(too weak)
ribosome
AMPA
AMPA
Ampakine
Mechanism 3
Excessive LTD
glu
Stronger connection
AMPA
glu
mGluR
ribosome
AMPA
AMPA
Fragile X
Immature connection
(too weak)
Lithium
blocks PI
turnover,
reduce
mGluR
signalling
through
PL-C/PK-C
cascade,
directly
block
protein
synthesis
by GSK3B
block
AMPA
mGluR
Li
ribosome
AMPA
AMPA
Lithium
Mechanism 1
Lithium and FXS Models
• Lithium corrects courtship memory deficits in
dfxr mutant fly – McBride 2005
• Lithium corrects open field hyperactivity and
decreases audiogenic seizures in fmr1 k/o
mouse - Bauschwitz
– FX-specific effect - lithium is convulsant in normals
• Corrects several learning tests, LTD in mouse
Li citrate dose titration
100
90
80
Data from R.
Bauschwitz
% total AGS
70
60
0 mg/kg
120 mg/kg
200 mg/kg
300 mg/kg
50
40
30
20
10
0
wt AGS
wt SE
FX AGS
(FVB background)
FX SE
Audiogenic Seizures
FXS Open-Label Lithium Trial
Average Scores on ABC-C Subtests for Subjects with
FXS During treatment with Lithium, n=11
• Test concept of mGluR pathway
inhibition
• 13 better at 2 mo, minimal toxicity
1 yr
70
Average ABC-C score
61.3
60
50
34.7
40
38.4
30
19.8
20
10
16
11.7
8.4 8.6
8
12.6 12.9
7
5.8
6.7
3.8 4.6
4.1 4.2
0
40
16
27
SD
Stereotypy SD Hyperactivity SD Inappropriate
4.5
7.6
Speech SD 2.7
Baseline
2 Month
Total SD 21.6
1 Year
12
-18
1
Group Mean
Change
-2
-5
-8
-20
-20
-25
-7
-22
10
8
8
7
6
-13
-15
-19
-40
Individual
Change
-44
-60
-67
ABC Total (range 0-174)
13 improved, p=0.005
Placebo change in CX516
study (N=25): -4
4
4
0
4
3
2
-2
-58
-80
Lethargy
6.6
14
20
0
Irritability SD
8.4
15
3
Group Mean
Change
Individual
Change
0
4
-1
-2
-4
RBANS List Learning (range 0-40)
8 of 10 improved, p= 0.028
CX516 placebo change: 0.0
Also significant improvement in CGI, VAS, and Vineland
Personal Daily Living Skills and Maladaptive Behavior
Lithium Study
Biomarker - ERK
Activation in
Lymphocytes
ERK phosphorylation
slower in K/O and FXS
Berry-Kravis et al, JDBP 2008
6
N=11
Baseline mean: 4.87 min
T1/2 Max Activation (Min)
5.5
5
2 Month Treatment mean:
4.11 min (p=0.007)
4.5
4
baseline
(about 1 min is difference
FXS and control)
3.5
3
2.5
2 mo
1 yr
2
1 Year Treatment mean:
3.56 min (P=0.00006)
New Targeted Treatments in Trials
- GABA Activators
• Data from FXS animal models
– GABA receptors abnormal
– Glutamate toxic to fragile X fly, GABA
activators rescue
• Baclofen (available, used for spasticity) GABA-A agonist that blocks presynaptic
release of glutamate
– Can help irritability in FXS and autism
– Reverses abnormal behaviors and seizures
in FXS mouse
– R form is much more active
R-Baclofen and the mGluR Theory –
Decrease Excessive Glutamatergic
Transmission
STX209
GABA-B
Proteins
Proteins
FMRP
Pre-synaptic
Post -synaptic
Mechanism 4
Clinical Trial of R-Baclofen
(STX209) in FXS
• Started in December
• Goal is to show improves
tantrums/aggression/agitation/irritability
• Placebo-controlled crossover with 4 weeks of
titrated treatment each arm
• Tests before and after treatment each arm
• Age 12 and up first 10 participants, now age 6
and up
• Extension – can get drug after trial if it works
• Good side effect profile
• Have seen some positives during trial thus far
New Targeted Treatments in
Trials - mGluR5 Blockers
• mGluR5 negative modulators = potent
anxiolytics, also anticonvulsant
• MPEP is prototype but not for humans
• Being developed for anxiety disorders,
neuropathic pain, irritable bowel
• Like lithium, would correct mGluR
overactivity in most areas of brain and
would correct oversynthesis of all FMRPregulated proteins
• Unlike lithium, specific for mGluR system
Stronger connection
Excessive LTD
glu
Ampakine
glu
AMPA
AMPA
mGluR
mGluR5 blockermGluR
Fenobam
Li
ribosome
ribosome
AMPA
AMPA
Fragile X
Immature connection
(too weak)
Combination: Fragile X
connection corrected
AMPA
AMPA
mGluR5
Blocker
Mechanism 1
AMPA Receptor Rescue by MPEP
Nakamoto et al. 2007
FMRP
Surface Internal
AMPA
AMPA
Control
FMRP Absent
FMRP Absent
and MPEP
GluR1 =
AMPA
receptors
that drive
strength of
neural
connections
ALL ABNORMAL Phenotypes
Tested in Fragile X Fly
Normalized by MPEP
• Courtship memory deficits McBride et al. 2005
• Mushroom body beta lobe fusion
• Lack of survival on commercial food
(glutamate-containing) Warren 2006
• Odor shock long-term memory deficits
Bolduc 2007
ALL ABNORMAL Phenotypes in
FXS Mouse Normalized by MPEP
(or Other mGluR5 Blockers)
Audiogenic seizures
Epileptiform bursts
Open field behavior
Prepulse inhibition
Dendritic spine shape
AMPA receptor internalization
Excessive protein synthesis
These and other phenotypes
in the fmr1 K/O mouse also
all reversed by crossing
fmr1 K/O to mGluR5
heterozygous mutant
Bauschwitz, 2006
Vehicle
n=5
100
% status epilepticus
•
•
•
•
•
•
•
SE107
80
n=6
60
40
n = 13
n = 10
20
0
FVB KO
Hybrid KO
Wong et al. 2006
MPEP Controls Audiogenic
Seizures in FXS Mouse
WE CAN
CURE
THE FXS
MOUSE!
Video courtesy of R. Bauschwitz PhD
But Mouse is not Man…
human
mouse
Human brain a lot more wiring time
mGluR5 Negative Modulators in
Development for FXS
• Fenobam
– Old molecule – No major toxicity
– Reduced anxiety in some adult phase II trials
– Dropped - short half life/erratic
pharmacokinetics (PK)
– Found to be mGluR5 blocker (Porter et al. 2005)
– 2008 – orphan drug status for FXS –
Neuropharm
– The first mGluR5 blocker used in FXS
FENOBAM
Open Label Escalating Single Dose
Trial of Fenobam in FXS
RUSH and UC Davis (Neuropharm and FRAXA) safety
trial of 1 dose (50-150 mg), 12 adult FXS (6M, 6F),
age 18-38, IQ 36-85
PPI improved 20% in 6/12 subjects
(control test-retest group 2/13, p=0.03)
Observation of positive behavioral
changes in 9/12 subjects
No fenobam-related adverse events
Prepulse Inhibition (PPI) Studies
50 ms 105 db white noise
Startle Alone Trials
Auditory stimulus
Latency
Amplitude (volts)
Obicularis
Oculi
EMG
Prepulse Trials
50 ms 105 db white noise
Prepulse: 50 ms, 75 db 1000Hz tone
Auditory stimuli
Prepulse interval:
60, 120, or 240 ms
Obicularis
Oculi
EMG
Amplitude (volts)
Prepulse Inhibition in Fragile X Syndrome:
Outcome Measure Ready for Treatment Trials
Hessl et al. AJMG 2008
Test-Retest Reliability
Group Effect: F(1, 74) = 36.00, p < 0.000001 !!
Alphas = .88 (control),
.85 (FXS), .89 overall!!!
PPI
improved
on
fenobam
Berry-Kravis et
al. JMG 2009
P=0.03
mGluR5 Negative Modulators in
Development for FXS
• STX107 – Seaside (from Merck)
– Good safety profile, twice daily dosing
– In Phase I - FXS trials projected in 2010
• AFQ056 – Novartis
– Good safety, twice daily dosing
– Randomized double-blind 28 day clinical trial
in Europe just finished – 30 males with FXS
– Test behavior and cognitive measures
– New trial planned in Europe
• Other companies developing for other
conditions (Addex, AstraZeneca)
mGluR5 Negative Modulators in
Development for FXS
• RO4917523 – Roche
– Once daily dosing, good safety
– Starts Phase II trial in USA November 2009
– Placebo controlled 6 week treatment
– 60 males or females with FXS age 18 up
– Cognitive, behavior measures, eye tracking,
PPI
– Lots of blood monitoring for PK
• 2 Phases - dose finding and max dose
• If safe and appears successful will
extend to 6-17 age group
Potential Other Future TRIALS
• Minocycline – Mechanism 2
• Better ampakines – Mechanism 3
• Multicenter Abilify trial for FXS
approval
• PAK inhibitors
• Combinations
Still need work on design and outcome measures
for these, many steps, but benefit may be overlap
with autism pathways – treatments for autism too
Minocycline
• Works on MMP9 – one of proteins regulated
by FMRP
• Too much MMP9 in FXS
• Minocycline inhibits the activity of the excess
MMP9
• Normalizes spines and some behaviors in
FXS mouse
• Anitibiotic used for zits – available now
– Causes teeth to turn yellow if used before age 10
– Trial in Canada
– Lots of use in USA – variable positives and
negatives – hard to interpret definitively
– Big trial planned through FXCRC
• Only affects one FMRP protein target so might
need to use with other things
New Measures of Function
“Outcome Measures”
for Clinical Trials
Alertness
KiTAP Test
- Many
subtests reliable in
test-retest – will use in
Roche study
- Correlates with attention
and hyperactivity
measures
- Crosses all levels
Go-no Go
Flexibility
Eye Tracker as New Outcome Measure
Validated this summer with test-retest to be ready
for Roche mGluR trial in Fall – measures eye
contact
NIH Study Shows Increased Rates of Cerebral
Protein Synthesis in Fragile X Knockout Mice
WT
KO
Qin et al (2005) J Neurosci 25:5087.
Current NIH Study to Prove Increased
Protein Synthesis in Humans with FXS
•
•
•
•
PET scans with anesthesia
FXS males over 18 years
All expenses paid to Washington
No medications (or if on stimulants can stop
for day of study)
• Will be very helpful in proving the mGluR
theory in humans and supporting the new
medication development
• Can be used to show the new meds work
Testing for
FXS
Modifiers
and
Biomarkers
Many proteins
in this pathway
may be
implicated in
autism
Making Stem Cells from Skin
Cells (iPS)
…and brain cells from the
stem cells for personal
brain cell cultures to
study treatment targets in
different people with FXS
Newborn Screening for Fragile X
Comes to 7th Grade
Pilot study on newborn
screening for FMR1
mutations using blood
spots:
a)
Identification of the frequencies and
the allele size distribution of the FMR1
premutation and full mutation alleles
Assessment of the severity of clinical
involvement during early development
for newborn probands with premutation
and full mutation alleles
To document the degree of clinical
involvement of the wide variety of
fragile X-related phenotypes in the
extended family of the newborn
proband identified by newborn
screening.
a)
The CGG linker protocol allows the detection of
expanded alleles in both males and females
c
f
CGG
repeat
1
5
2
Lane
3
4
b)
(GCC)n
c
f
CGG
repeat
Consent forms and
information sheets approved
by IRBs and being presented
to each mother delivering a
baby at Rush (Chicago) and
UC Davis (Sacramento) since
October 1, 2008
Sacramento and Chicago:
2000 blood spots collected
Newborn
Screening for FXS
Pilot program (30,000 births) in
California, Illinois
• Need follow up for positives with early intervention and
genetic counseling at FXS clinic
• Benefits
–
–
–
–
in early intervention right away
avoid long process of diagnosis, extra tests
avoid second (or third) affected child
get diagnosis for symptomatic premutation carriers through
cascade analysis of family
• Problems
– what to do with asymptomatic premutation carriers
– no cure
• If new treatments give partial “cure” – newborn screening
will be key (treatments may work better earlier)
Pilot FXS Newborn Screening
• Will address epidemiology issues (eg.
mutation frequencies)
• Will address developmental questions
(natural history of development and early
intervention in pre and full mutation
carriers)
• Will address whether screening and
diagnosis is helpful or not for families
FXCRC Registry and Database
• National Registry to find people who want to
be involved in research and clinical trials –
going up Fall 2009
• Database on participants with FXS entered to
answer important questions about the
disorder – hopefully up Summer 2010
• Enroll at any FXS Clinic – OHIO Clinic
• De-identified at national level – names of
participants kept at Fragile X Clinics
• Can specify types of research can do
• Need to sign consent for each person entered
• For registry: one page form to fill out for each
person – self and relative forms
Acknowledgements
• FRAXA Research
Foundation
• NIH – NINDS
• Kiwanis Spastic Paralysis
Foundation
• National Fragile X
Foundation
•
–
•
•
Sue Ellen Krause PhD
Sandy Block MS
Steve Guter MS
Ed Cook MD
Randi Hagerman MD
Maureen Leehey MD
Paul Hagerman MD PhD
Chris Goetz MD
Don Bailey PhD
Glenn Stebbins PhD
Pete Van der Klish PhD
•
FXS Families
Kristina Potanos
Dahlia Weinberg
Rebecca Lara
Foster Lewin
Allison Sumis
Crystal Hervey
Students
–
–
–
–
Steve Porges PhD
Mina Johnson PhD
Isabel Boutet PhD
•
Steve Hooper PhD
Ivan Jean Weiler PhD
Bill Greenough PhD
•
Ning Weng PhD
Mark Bear PhD
Emily Osterweil PhD •
Lili Zhou MD
Study Co-ordinators
–
–
–
–
–
–
• Collaborators
–
–
–
–
–
–
–
–
–
–
–
Lab Research Associate
Ok-Kyung Kim
Chinton DeSai
Ravi Iyengar
Hazel Perry
Statistics
–
–
Sue Leurgans PhD
Joanna Wuu MS
Cortex Pharmaceuticals
–
–
Steve Johnson PhD
Roger Stoll PhD
Seaside Pharmaceuticals
–
Randy Carpenter PhD
Study Co-ordinators off site
–
–
–
Tristan Jardini
Penelope Decle
Jennifer Cogswell