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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 • Increase Brain BDNF to Attenuate Rett Symptoms Chang et al, 2006. Neuron 49, 341–348 Wang et al, 2006. J Neurosci 26:10911–5 2 BDNF – A Major Regulator of Synaptic Plasticity • Synthesized and stored in glutamatergic neurons and is released in an activitydependent 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 3 Strategy • Treat with AMPAKINE Molecules to Increase Endogenous BDNF Levels in Specific Brain Regions – AMPAKINEs are small molecules that positively modulate the AMPA receptor 4 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 5 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 1 ms Pulse Baseline Deactivation + AMPAKINE Superimposed Desensitization 500 ms Pulse Baseline + AMPAKINE Superimposed 6 AMPAKINEs Have Acute and Chronic Effects In Vivo AMPAKINE Treatment Acute Effects Chronic Effects (Lasts with the t½ of the drug) (Trophic induction lasting ≥ one day) • Memory • Cognition • Psychiatric disorders • • • • Memory Cognition Psychiatric disorders Degenerative diseases 7 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 8 Chronic Effects of AMPAKINEs on BDNF Rat Cortical Cultures Cultured Hippocampal Slices In Vivo 0.30 0.25 0.20 0.15 0.10 0.05 0.00 Protein mRNA Protein 6 hr AMPAKINE pulse, protein at 24 hrs 3 hr AMPAKINE pulse, mRNA at 18 hrs 1 injection/day for 7 days, Hippocampus collected 24 hrs after last treatment 9 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 10 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 11 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 12 CX929 Up-regulates Mature BDNF in HD Knock-in Mice and Restores LTP Mature Hippocampal BDNF Protein Hippocampal LTP 140 % Control Mean 120 100 80 60 40 20 0 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 13 Current Studies • Evaluate if AMPAKINE treatment corrects Rett phenotypes in Mecp2-/y mice – Respiration – BDNF levels – Other behaviors 14 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 15
