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AMPAKINE Compounds for the Treatment of Rett Syndrome

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

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AMPAKINE Compounds for the Treatment of Rett Syndrome

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  1. AMPAKINE Compounds for the Treatment of Rett Syndrome Mark A Varney Chief Scientific Officer

  2. 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, 341–348 Wang et al, 2006. J Neurosci 26:10911–5

  3. 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

  4. Strategy • Treat with AMPAKINE Molecules to Increase Endogenous BDNF Levels in Specific Brain Regions • AMPAKINEs are small molecules that positively modulate the AMPA receptor

  5. 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

  6. 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

  7. AMPAKINEs Have Acute and Chronic Effects In Vivo 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

  8. Chronic Effects of AMPAKINEs 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

  9. 0.30 0.25 0.20 0.15 0.10 0.05 0.00 Ctrl 10uM CX929 25uM CX929 50uM CX929 100uM CX929 Chronic Effects of AMPAKINEs on BDNF Rat Cortical Cultures Cultured Hippocampal Slices In Vivo Protein 6 hr AMPAKINE pulse, protein at 24 hrs mRNA 3 hr AMPAKINE pulse, mRNA at 18 hrs Protein 1 injection/day for 7 days, Hippocampus collected 24 hrs after last treatment

  10. 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

  11. Reduced BDNF and Defective LTP in Asymptomatic HD Knock-in Mice TBS: 10 bursts of 4 pulses 100 Hz; separated by 200 msec Lynch et al., J. Neurosci 2007

  12. AMPAKINE Treatment Paradigm HD Knock-in Mice CX929 selected because of its short t½ of 15min and robust effects on BDNF 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

  13. CX929 Up-regulates Mature BDNF in HD Knock-in Mice and Restores LTP Mature Hippocampal BDNF Protein Hippocampal LTP Normal HD HD+CX929 • Cognitive deficits restored and motor deficits prevented by CX929 Mature hippocampal BDNF and LTP assayed 18 hrs after the last of 30 daily treatments with CX929

  14. Current Studies • Evaluate if AMPAKINE treatment corrects Rett phenotypes in Mecp2-/y mice • Respiration • BDNF levels • Other behaviors

  15. 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

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