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AMPAKINE Compounds for the Treatment of Rett Syndrome. Mark A Varney Chief Scientific Officer. Hypothesis. Depressed Levels of BNDF Contribute to the Phenotype of Rett Syndrome Lifespan Motor Activity Cortical Layer V Firing Breathing Abnormalities - PowerPoint PPT Presentation
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AMPAKINE Compounds for the Treatment of Rett Syndrome
Mark A VarneyChief Scientific Officer
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Hypothesis
• Depressed Levels of BNDF Contribute to the Phenotype of Rett Syndrome – Lifespan
– Motor Activity
– Cortical Layer V Firing
– Breathing Abnormalities
• Increase Brain BDNF to Attenuate Rett Symptoms
Chang et al, 2006. Neuron 49, 341–348Wang et al, 2006. J Neurosci 26:10911–5
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BDNF – A Major Regulator of SynapticPlasticity
• Synthesized and stored in glutamatergic neurons and is released in an activity-dependent manner
• Critical for neuronal survival and differentiation
• Plays a role in fast excitatory synaptic transmission and synaptic plasticity, including LTP and LTD
• Critical for synaptic plasticity and memory processing in the adult brain
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Strategy
• Treat with AMPAKINE Molecules to Increase Endogenous BDNF Levels in Specific Brain Regions– AMPAKINEs are small molecules that
positively modulate the AMPA receptor
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AMPA Receptors Play a Key Role in Glutamatergic Transmission
• Glutamate is the major excitatory neurotransmitter in the CNS
• Virtually all neurons express glutamate receptors
• Fast excitatory transmission is mediated by AMPA receptors
Swanson et al. (2005)Nat Rev Drug Dis 41: 131-144
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AMPAKINE Molecules
• AMPA receptors deactivate and/or desensitize extremely rapidly (~2-10 ms)
• AMPAKINEs are allosteric positive modulators of the AMPA receptor
– Attenuate deactivation and/or desensitization of AMPA receptors
– Strengthen synaptic transmission and facilitate long term potentiation (LTP), widely regarded as the substrate for memory
– Stimulate BDNF production
Deactivation Desensitization1 ms Pulse 500 ms Pulse
Baseline + AMPAKINE Superimposed Baseline + AMPAKINE Superimposed
Deactivation Desensitization1 ms Pulse 500 ms Pulse
Baseline + AMPAKINE Superimposed Baseline + AMPAKINE Superimposed
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AMPAKINE Treatment
Acute Effects
(Lasts with the t½ of the drug)
•Memory •Cognition•Psychiatric disorders
Chronic Effects
(Trophic induction lasting
≥ one day)
•Memory •Cognition•Psychiatric disorders•Degenerative diseases
AMPAKINEs Have Acute and Chronic Effects In Vivo
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1. Brief treatment with
AMPAKINE causes long
lasting increases in BDNF
2. Use daily injections of short half-life AMPAKINEs to
chronically increase BDNF levels.
3. BDNF then promotes plasticity and neuronal viability
Chronic Effects of AMPAKINEs
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Chronic Effects of AMPAKINEs on BDNF
Rat Cortical Cultures Cultured Hippocampal Slices In Vivo
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Ctrl
10uM
CX92
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25uM
CX92
9
50uM
CX92
9
100u
M C
X929
mRNA
3 hr AMPAKINE pulse, mRNA at 18 hrs
Protein
1 injection/day for 7 days, Hippocampus collected 24
hrs after last treatment
Protein
6 hr AMPAKINE pulse, protein at 24 hrs
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Huntington’s Disease (HD)
• Progressive, hereditary brain disease that causes changes in movement, thinking and behavior
• Onset commonly between ages 30-50• 30,000 people in US (~1/10,000)• Caused by excessive CAG repeats in the
huntingtin gene • Disturbances in executive function are
probably earliest manifestation• Neuropathology, particularly in striatum, in
later phases• BDNF levels are reduced in HD postmortem
brain and transgenic mouse models
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Reduced BDNF and Defective LTP in Asymptomatic HD Knock-in Mice
Lynch et al., J. Neurosci 2007
TBS: 10 bursts of 4 pulses 100 Hz; separated by 200 msec
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AMPAKINE Treatment Paradigm
HD Knock-in Mice
Injected with Vehicle or CX929 at 5 mg/kg/day i.p. for
between 4 to 30 days
18-24 hours after the last dose, measure•Hippocampal LTP•Actin Polymerization•Locomotor Effects•BDNF Measurements•Cognition
CX929 selected because of its short t½ of 15min and robust effects on BDNF
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CX929 Up-regulates Mature BDNF in HD Knock-in Mice and Restores LTP
Mature hippocampal BDNF and LTP assayed 18 hrs after the last of 30 daily treatments with CX929
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20
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80
100
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% C
ontr
ol M
ea
n
Normal HD HD+CX929
Mature HippocampalBDNF Protein
Hippocampal LTP
•Cognitive deficits restored and motor deficits prevented by CX929
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Current Studies
• Evaluate if AMPAKINE treatment corrects Rett phenotypes in Mecp2-/y mice– Respiration
– BDNF levels
– Other behaviors
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Summary
• AMPAKINE molecules increase brain BDNF levels
• Transgenic HD mice have deficits in BDNF levels and deficits in hippocampal LTP– The short acting AMPAKINE, CX929 can restore
depressed BDNF levels and hippocampal LTP deficits
• Rett Mice have deficits in BDNF
• Currently testing AMPAKINEs in Rett mice to see if it restores normal phenotype