creb & the development of novel memory enhancers tim tully chief science officer dart...
TRANSCRIPT
![Page 1: CREB & The Development Of Novel Memory Enhancers Tim Tully Chief Science Officer Dart Neuroscience LLC](https://reader036.vdocuments.mx/reader036/viewer/2022062716/56649dc65503460f94abb45e/html5/thumbnails/1.jpg)
CREB & The DevelopmentOf Novel Memory Enhancers
Tim TullyChief Science Officer
Dart Neuroscience LLC
![Page 2: CREB & The Development Of Novel Memory Enhancers Tim Tully Chief Science Officer Dart Neuroscience LLC](https://reader036.vdocuments.mx/reader036/viewer/2022062716/56649dc65503460f94abb45e/html5/thumbnails/2.jpg)
765432100
20
40
60
80
100
10x spaced
10x massed1x
RETENTION TIME (day)
PER
FO
RM
AN
CE
IN
DEX
Long-Term MemoryIn The Fruit Fly
Tully et al (1994)
![Page 3: CREB & The Development Of Novel Memory Enhancers Tim Tully Chief Science Officer Dart Neuroscience LLC](https://reader036.vdocuments.mx/reader036/viewer/2022062716/56649dc65503460f94abb45e/html5/thumbnails/3.jpg)
PER
FO
RM
AN
CE I
ND
EX
TIME (days)
hs-dCREB2-rmassed
spaced
0
20
40
60
80
100
-20
1 3 5 7
CREB RepressorBlocks LTM
Yin et al (1994)
See also: Bourtchouladze et al (1994)
![Page 4: CREB & The Development Of Novel Memory Enhancers Tim Tully Chief Science Officer Dart Neuroscience LLC](https://reader036.vdocuments.mx/reader036/viewer/2022062716/56649dc65503460f94abb45e/html5/thumbnails/4.jpg)
0
10
20
30
40
50 control
CREB-a
1x 10x spaced
7-D
AY
MEM
OR
Y
TRAINING SESSIONS
CREB ActivatorEnhances Memory
Yin etal. (1995)
![Page 5: CREB & The Development Of Novel Memory Enhancers Tim Tully Chief Science Officer Dart Neuroscience LLC](https://reader036.vdocuments.mx/reader036/viewer/2022062716/56649dc65503460f94abb45e/html5/thumbnails/5.jpg)
dCREB2 Homologs
Olson etal (2005)
GENESEER
![Page 6: CREB & The Development Of Novel Memory Enhancers Tim Tully Chief Science Officer Dart Neuroscience LLC](https://reader036.vdocuments.mx/reader036/viewer/2022062716/56649dc65503460f94abb45e/html5/thumbnails/6.jpg)
Drug ScreenFor Enhancers of CREB
ATP
cAMP
AMP
AC
PDE PKA
Ca/CaM
CRE
CREB luciferase
nucleus
forskolin
neuroblastoma cell
HT-0712
![Page 7: CREB & The Development Of Novel Memory Enhancers Tim Tully Chief Science Officer Dart Neuroscience LLC](https://reader036.vdocuments.mx/reader036/viewer/2022062716/56649dc65503460f94abb45e/html5/thumbnails/7.jpg)
0
10
20
30
40
50
60
Mem
ory
Score
Vehicle
0.1mg/kg HT0712(60’ after)
*
8 8 8 8
Memory EnhancementIn Normal, Young Mice
2 Trials 5 Trials
![Page 8: CREB & The Development Of Novel Memory Enhancers Tim Tully Chief Science Officer Dart Neuroscience LLC](https://reader036.vdocuments.mx/reader036/viewer/2022062716/56649dc65503460f94abb45e/html5/thumbnails/8.jpg)
Paired-Associate MemoryIn Elderly Macaque
0
5
10
15
20
25
30
vehicle
Tra
inin
g D
ays
to C
rite
rion
1 mg/kg 10 mg/kg 100 mg/kg
![Page 9: CREB & The Development Of Novel Memory Enhancers Tim Tully Chief Science Officer Dart Neuroscience LLC](https://reader036.vdocuments.mx/reader036/viewer/2022062716/56649dc65503460f94abb45e/html5/thumbnails/9.jpg)
Mouse Model Of Rubinstein-Taybi Syndrome
wild-type (sib) CBP+/- mice
Oike etal (1999)
![Page 10: CREB & The Development Of Novel Memory Enhancers Tim Tully Chief Science Officer Dart Neuroscience LLC](https://reader036.vdocuments.mx/reader036/viewer/2022062716/56649dc65503460f94abb45e/html5/thumbnails/10.jpg)
15-min Training
Facilitation Of LTMIn RTS Model
Vehicle HT0712(0.1 mg/kg)
*
wt
CBP+/ -
80
70
60
50
40
30
20
10
0
-10
Mem
ory
Score
Bourtchouladze etal (2003)
![Page 11: CREB & The Development Of Novel Memory Enhancers Tim Tully Chief Science Officer Dart Neuroscience LLC](https://reader036.vdocuments.mx/reader036/viewer/2022062716/56649dc65503460f94abb45e/html5/thumbnails/11.jpg)
Facilitation Of RehabilitationAfter Stroke
Post
-str
oke
moto
r re
covery
Day
0
0.5
1.0
1.5
0 1 2 3 4 5 6 7 8 9 10 11
vehicle
HT-0712(0.15 mg/kg )
MacDonald et al. (2007) Neurorehabil. Neural Repair 6: 486.
![Page 12: CREB & The Development Of Novel Memory Enhancers Tim Tully Chief Science Officer Dart Neuroscience LLC](https://reader036.vdocuments.mx/reader036/viewer/2022062716/56649dc65503460f94abb45e/html5/thumbnails/12.jpg)
Cognitive RehabilitationAfter Traumatic Brain Injury
Hallam etal (2010) unpublished.
![Page 13: CREB & The Development Of Novel Memory Enhancers Tim Tully Chief Science Officer Dart Neuroscience LLC](https://reader036.vdocuments.mx/reader036/viewer/2022062716/56649dc65503460f94abb45e/html5/thumbnails/13.jpg)
Cognitive RehabGeneralizes
Hallam etal (2010) unpublished.
![Page 14: CREB & The Development Of Novel Memory Enhancers Tim Tully Chief Science Officer Dart Neuroscience LLC](https://reader036.vdocuments.mx/reader036/viewer/2022062716/56649dc65503460f94abb45e/html5/thumbnails/14.jpg)
Clinical Safety
Phase 1 (single rising dose)• 42 healthy young and elderly exposed (405 mg max dose)• no serious adverse events
Phase 1 (repeat dose)• 24 healthy young and elderly exposed (135 mg max dose)• no serious adverse events
Phase 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
![Page 15: CREB & The Development Of Novel Memory Enhancers Tim Tully Chief Science Officer Dart Neuroscience LLC](https://reader036.vdocuments.mx/reader036/viewer/2022062716/56649dc65503460f94abb45e/html5/thumbnails/15.jpg)
Project ResearchPre-
ClinicalPhase I Phase II Phase III
PDE4
GalR3
MAO-B
GABA-A
Novel
GLYT1
Drug Development Pipeline
HT-2157
BackUp
Back-ups
HT-1067
BackUp
Back-ups
Hits
Screening
HT-4313
HT-0712
Screening
Hits
![Page 16: CREB & The Development Of Novel Memory Enhancers Tim Tully Chief Science Officer Dart Neuroscience LLC](https://reader036.vdocuments.mx/reader036/viewer/2022062716/56649dc65503460f94abb45e/html5/thumbnails/16.jpg)
Acknowlegements
Ken Johns CEOPhil Perera CMOAnne Danks Director, Preclinical DevelopmentAlan Kaplan Director, ChemistryTim Tully Founder, x-CSO
Lila Davachi NYUEmmanuel DeCamp TJUJeff Kleim UF-Gainesville
Collaborators
![Page 17: CREB & The Development Of Novel Memory Enhancers Tim Tully Chief Science Officer Dart Neuroscience LLC](https://reader036.vdocuments.mx/reader036/viewer/2022062716/56649dc65503460f94abb45e/html5/thumbnails/17.jpg)
HT-0712 FacilitatesMotor Rehab After TBI
Hallam etal (2010) unpublished.
![Page 18: CREB & The Development Of Novel Memory Enhancers Tim Tully Chief Science Officer Dart Neuroscience LLC](https://reader036.vdocuments.mx/reader036/viewer/2022062716/56649dc65503460f94abb45e/html5/thumbnails/18.jpg)
HT-0712 FacilitatesCognitive Rehab After TBI
Hallam etal (2010) unpublished.
![Page 19: CREB & The Development Of Novel Memory Enhancers Tim Tully Chief Science Officer Dart Neuroscience LLC](https://reader036.vdocuments.mx/reader036/viewer/2022062716/56649dc65503460f94abb45e/html5/thumbnails/19.jpg)
Drug AloneDoes Not Facilitate
Hallam etal (2010) unpublished.
![Page 20: CREB & The Development Of Novel Memory Enhancers Tim Tully Chief Science Officer Dart Neuroscience LLC](https://reader036.vdocuments.mx/reader036/viewer/2022062716/56649dc65503460f94abb45e/html5/thumbnails/20.jpg)
MEM
OR
Y R
ETEN
TIO
N
0 1 3 5 24TIME (hr)
STM
MTM
ARM LTM
observed
No Measures Of Long-Term MemoryIn The Clinic…
clinical measures of dementia
![Page 21: CREB & The Development Of Novel Memory Enhancers Tim Tully Chief Science Officer Dart Neuroscience LLC](https://reader036.vdocuments.mx/reader036/viewer/2022062716/56649dc65503460f94abb45e/html5/thumbnails/21.jpg)
0 15 45 60 90-30-20-100
7d - 7hrDose (mg)
P = 0.22P = 0.03P = 0.32P = 0.20
7-Day WordRecallIn Humans With AAMI