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CREB & The Development Of Novel Memory Enhancers

CREB & The Development Of Novel Memory Enhancers. Tim Tully Chief Science Officer Dart Neuroscience LLC. 0. 1. 2. 3. 4. 5. 6. 7. Long-Term Memory In The Fruit Fly. 100. 80. 60. PERFORMANCE INDEX. 10x spaced. 40. 10x massed. 20. 1x. 0. RETENTION TIME (day).

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CREB & The Development Of Novel Memory Enhancers

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  1. CREB & The DevelopmentOf Novel Memory Enhancers Tim Tully Chief Science Officer Dart Neuroscience LLC

  2. 0 1 2 3 4 5 6 7 Long-Term MemoryIn The Fruit Fly 100 80 60 PERFORMANCE INDEX 10x spaced 40 10x massed 20 1x 0 RETENTION TIME (day) Tully et al (1994)

  3. CREB RepressorBlocks LTM 100 80 60 spaced PERFORMANCE INDEX 40 20 hs-dCREB2-r massed 0 -20 7 3 5 1 TIME (days) Yin et al (1994) See also: Bourtchouladze et al (1994)

  4. CREB ActivatorEnhances Memory control 5 0 CREB-a 4 0 3 0 7-DAY MEMORY 2 0 1 0 0 10x spaced 1x TRAINING SESSIONS Yin etal. (1995)

  5. dCREB2 Homologs GENESEER Olson etal (2005)

  6. HT-0712 Drug ScreenFor Enhancers of CREB forskolin neuroblastoma cell ATP Ca/CaM AC cAMP PDE PKA AMP nucleus luciferase CREB CRE

  7. Memory EnhancementIn Normal, Young Mice Vehicle 60 0.1mg/kg HT0712 (60’ after) 50 40 * Memory Score 30 20 8 8 8 8 10 0 5 Trials 2 Trials

  8. Paired-Associate MemoryIn Elderly Macaque 30 25 20 Training Days to Criterion 15 10 5 0 1 mg/kg 10 mg/kg 100 mg/kg vehicle

  9. Mouse Model Of Rubinstein-Taybi Syndrome CBP+/- mice wild-type (sib) Oike etal (1999)

  10. Facilitation Of LTM In RTS Model 15-min Training 80 w t 70 + / - C B P 60 50 40 Memory Score * 30 20 10 0 -10 V e h i c l e H T 0 7 1 2 ( 0 . 1 m g / k g ) Bourtchouladze etal (2003)

  11. Facilitation Of RehabilitationAfter Stroke 1.5 vehicle 1.0 HT-0712 (0.15 mg/kg ) Post-stroke motor recovery 0.5 0 0 1 2 3 4 5 6 7 8 9 10 11 Day MacDonald et al. (2007) Neurorehabil. Neural Repair 6: 486.

  12. Cognitive RehabilitationAfter Traumatic Brain Injury Hallam etal (2010) unpublished.

  13. Cognitive RehabGeneralizes Hallam etal (2010) unpublished.

  14. Clinical Safety Phase 1 (single rising dose)• 42 healthy young and elderly exposed (405 mg max dose) • no serious adverse eventsPhase 1 (repeat dose)• 24 healthy young and elderly exposed (135 mg max dose) • no serious adverse eventsPhase 1 (interaction with warfarin) • 21 elderly exposed (45 mg dose) • no serious adverse events Phase 2a (28 daily doses)• 55 elderly with AAMI (90 mg max dose) • no serious adverse events

  15. Drug Development Pipeline HT-0712 BackUp HT-2157 BackUp HT-1067 Back-ups HT-4313 Back-ups Hits Screening Hits Screening

  16. Acknowlegements Ken Johns CEO Phil Perera CMO Anne Danks Director, Preclinical Development Alan Kaplan Director, Chemistry Tim Tully Founder, x-CSO Lila Davachi NYU Emmanuel DeCamp TJU Jeff Kleim UF-Gainesville Collaborators

  17. HT-0712 FacilitatesMotor Rehab After TBI Hallam etal (2010) unpublished.

  18. HT-0712 FacilitatesCognitive Rehab After TBI Hallam etal (2010) unpublished.

  19. Drug Alone Does Not Facilitate Hallam etal (2010) unpublished.

  20. No Measures Of Long-Term MemoryIn The Clinic… clinical measures of dementia STM observed MEMORY RETENTION ARM LTM MTM 24 3 0 1 5 TIME (hr)

  21. 7-Day WordRecallIn Humans With AAMI

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