CREB & The Development
Of Novel Memory Enhancers
Tim Tully
Chief Science Officer
Dart Neuroscience LLC
Long-Term Memory
In The Fruit Fly
PERFORMANCE INDEX
100
80
60
10x spaced
40
10x massed
20
1x
0
0
1
2
3
4
5
RETENTION TIME (day)
6
7
Tully et al (1994)
CREB Repressor
Blocks LTM
100
PERFORMANCE INDEX
80
60
spaced
40
20
0
hs-dCREB2-r
massed
-20
1
3
5
7
TIME (days)
Yin et al (1994)
See also: Bourtchouladze et al (1994)
CREB Activator
Enhances Memory
7-DAY MEMORY
50
control
CREB-a
40
30
20
10
0
1x
10x spaced
TRAINING SESSIONS
Yin etal. (1995)
dCREB2 Homologs
GENESEER
Olson etal (2005)
Drug Screen
For Enhancers of CREB
forskolin
neuroblastoma cell
ATP
AC
Ca/CaM
cAMP
PKA
HT-0712
PDE
AMP
nucleus
CREB
CRE
luciferase
Memory Enhancement
In Normal, Young Mice
Vehicle
60
0.1mg/kg HT0712
(60’ after)
Memory Score
50
40
30
*
20
10
8
8
8
8
0
2 Trials
5 Trials
Paired-Associate Memory
In Elderly Macaque
30
Training Days to Criterion
25
20
15
10
5
0
vehicle
1 mg/kg
10 mg/kg
100 mg/kg
Mouse Model Of
Rubinstein-Taybi Syndrome
wild-type (sib)
CBP+/- mice
Oike etal (1999)
Facilitation Of LTM
In RTS Model
15-min Training
80
wt
70
CBP+ / -
Memory Score
60
50
40
30
*
20
10
0
-10
Ve hic le
HT0712
(0 .1 m g /kg )
Bourtchouladze etal (2003)
Facilitation Of Rehabilitation
After Stroke
Post-stroke motor recovery
1.5
vehicle
1.0
HT-0712
(0.15 mg/kg )
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.
Cognitive Rehabilitation
After Traumatic Brain Injury
Hallam etal (2010) unpublished.
Cognitive Rehab
Generalizes
Hallam etal (2010) unpublished.
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
Drug Development Pipeline
Project
PDE4
PreClinical
Research
GABA-A
Novel
GLYT1
Phase II
Phase III
HT-0712
BackUp
HT-2157
GalR3
MAO-B
Phase I
BackUp
HT-1067
Back-ups
HT-4313
Back-ups
Hits
Screening
Hits
Screening
Acknowlegements
Collaborators
Ken Johns
Phil Perera
Anne Danks
Alan Kaplan
Tim Tully
CEO
CMO
Director, Preclinical Development
Director, Chemistry
Founder, x-CSO
Lila Davachi
Emmanuel DeCamp TJU
Jeff Kleim
NYU
UF-Gainesville
HT-0712 Facilitates
Motor Rehab After TBI
Hallam etal (2010) unpublished.
HT-0712 Facilitates
Cognitive Rehab After TBI
Hallam etal (2010) unpublished.
Drug Alone
Does Not Facilitate
Hallam etal (2010) unpublished.
No Measures Of Long-Term Memory
In The Clinic…
MEMORY RETENTION
clinical measures of dementia
STM
observed
ARM
LTM
MTM
0
1
3
TIME (hr)
5
24
7-Day WordRecall
In Humans With AAMI
P = 0.22
P = 0.03
P = 0.32
P = 0.20
7d - 7hr
0
-10
-20
-30
0
15
45
Dose (mg)
60
90