Download Theodore-SSADH - SSADH Association

Succinic Semi-aldehyde
Dehydrogenase Deficiency:
Human Pathophysiology and Clinical
Trial
William H Theodore MD
Chief, Clinical Epilepsy Section
NINDS NIH
Disclosures
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Bench to Bedside program
SSADH Association
NINDS DIR
Normal GABA Pathway
SSADH Deficiency
GABA and GHB
GABA
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Up to 1/3 brain synapses use
GABA
Modulates most brain
inhibition.
Why does increased GABA
cause seizures?
Paradoxical receptor
function?
downregulation of receptors
GHB
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Modulates arousal
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Drug of
abuse/amnesia/assault
Causes seizures in animals
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Rx for narcolepsy
Human cases reported
Effects on multiple
neurotransmitter systems:
dopamine, serotonin,
acetylcholine, GABA, GHB
GABA Receptors
GABAA-ρ
GHB targets GABAB Receptors at high
concentrations
The GABA/GHBergic synapse,
highlighting different low- and
high-affinity targets for GHB.
The metabotropic GABAB
receptors are activated by
millimolar GHB. Elusive GHB
high-affinity sites are activated
by nM to mM GHB, consistent
with normal endogenous
concentrations.
Courtesy of KM Gibson
Possible SSADH Deficiency
Pathophysiology
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Presynaptic activation of GABABR autoreceptors on GABAergic
neurons and heteroreceptors inhibit neurotransmitter release
Postsynaptic GABABR activation produces slow inhibitory
postsynaptic potentials via G protein–coupled inward rectifying
potassium channels.
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GABABR-mediated late long-lasting potassium-dependent IPSPs activate lowthreshold calcium potentials, burst firing, oscillatory behavior in thalamic neurons
GABABR agonists exacerbate absence seizures in several animal models,
blocked by specific antagonists
Combined effects of GHB, GABA on GABABR, GHBR, oxidative
stress, possibly other neurotransmitters?
Wong et al 2003
GHB Induces Spiking in
Macaques
Snead 1978
SSADH:
From animal model to patients
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In SSADH -/- mice
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Increased GABA, GHB levels
Reduced brain GABA binding
down-regulation of post-synaptic GABA receptors
Hypotheses:
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Patients but not parents (carriers) will have:
Decreased 11C-flumazenil PET BP
Increased cortical excitability
MR Spectroscopy in SSADH Deficiency
SSADH
GLU/GLUT
Control
Novotny et al 2003
SSADH DEFICIENCY
T2-weighted MRI
Globus Pallidus Signal Hyperintensity; Cerebellar Atrophy
Human and Mouse Cerebellar Atrophy
Acosta et al 2010
GABAAR Mediated Mechanisms in SSADH:
decreased TBPS binding
Wu et al. Ann Neurol 2006;59:42–52
SSADH Deficiency:
11C-FMZ
Patient
Binding but not Delivery Reduced
Carrier
Neurology 2009
Tracer Delivery
11C-FMZ
PET showed Reduced GABAA
Receptor Binding in SSADH Deficiency
*
#
#
*
*
#
•*p< 0.001
•#p<0.02
Neurology 2009;
Brain [11C] Flumazenil Binding Potential (BPND):
Patients, Parents, and Healthy Controls
Neurology 2009
SSADH Deficiency: Potential Therapeutic Targets
Dev Med Child Neurol 2015
Pertinent Structures
SGS-742 and GABAergic Transmission
Presynaptic GABABR activation: inhibition of transmitter release from inhibitory and
excitatory terminals. SGS-742 (preferential presynaptic blockade) enhanced GABA
release in rat cerebral cortex slices.
SGS-742 Effect on Seizures in Mouse Model
J Inherit Metab Dis 2009
800
600
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kg
m
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SG
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kg
g/
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spike-wave duration (sec)
Effect of SGS-742 on Seizures in SSADH
Deficient Mice
mouse group (n=4)
SGS-742 Trial Rationale
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GHB Activation of presynaptic GABAB receptors causes an inhibition of
neurotransmitter release from both inhibitory and excitatory terminals
High GABA and GHB levels desensitize postsynaptic, but not presynaptic,
GABAB receptors
SGS-742 is a of GABAB receptor antagonist
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In SSADH animal models, leads to preferential presynaptic blockade
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should lead to preferential presynaptic GABABR blockade
Enhanced release of GABA in electrically stimulated rat cerebral cortex slices.
Reduced seizures, prolonged life
In ‘normal’ animals, improved cognitive performance
significant improvement in adult mild cognitive
impairment study
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Good safety and tolerability
Possible Action of SGS-742
SGS-742
Presynaptic
GABAb receptor
GABAergic
neuron
Presynaptic
GABAb receptor
GABAergic
neuron
SGS-742 Side Effects
Adult Mild Cognitive Impairment Trial
Side effect
SGS-742 (%)
Placebo (%)
Diarrhea
8
9
Nausea
8
6
Joint pain
5
3
Dizziness
7
3
Headache
4
11
Rash
1
0
Agitation/irritability
2
0
Sleepiness
2
0
(Froestl et al., 2004, Tomlinson et al 2004)
SGS-742 Pharmacokinetics
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drug absorption rapid, peak plasma
concentration within 4 hours of single oral
doses
99% excreted unchanged in urine
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Low interaction potential
Half-life 4 hours
Trial of SGS-742
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Patients 8 and older
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Amendment submitted to reduce low age limit to 4
Blinded placebo-controlled crossover
10 mg/kg/dose (up to 600 mg) tid (target dose).
Clinical, cognitive, TMS outcome measures
Magnetic Resonance Imaging to measure GABA
CSF analyses
NCT 02019667
SGS-742 Study
Conclusions
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Importance of Collaboration
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Involvement of patients and families
Value of animal models for understanding human
disease
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extramural basic scientists, child neurologists
Imaging, clinical neurophysiology studies to show match between
them
Rare diseases could have wider impact:
Possible application to Down’s syndrome?
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Kleschevnikov et al J Neurosci 2012: Deficits in Cognition and Synaptic Plasticity in a Mouse
Model of Down Syndrome Ameliorated by GABAB Receptor Antagonists