CREB & The Development Of Novel Memory Enhancers

CREB & The DevelopmentOf Novel Memory Enhancers

Tim TullyChief Science Officer

Dart Neuroscience LLC

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)

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)

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)

dCREB2 Homologs

Olson etal (2005)

GENESEER

Drug ScreenFor Enhancers of CREB

ATP

cAMP

AMP

AC

PDE PKA

Ca/CaM

CRE

CREB luciferase

nucleus

forskolin

neuroblastoma cell

HT-0712

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

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

Mouse Model Of Rubinstein-Taybi Syndrome

wild-type (sib) CBP+/- mice

Oike etal (1999)

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)

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.

Cognitive RehabilitationAfter Traumatic Brain Injury

Hallam etal (2010) unpublished.

Cognitive RehabGeneralizes

Hallam etal (2010) unpublished.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

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

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

HT-0712 FacilitatesMotor Rehab After TBI

Hallam etal (2010) unpublished.

HT-0712 FacilitatesCognitive Rehab After TBI

Hallam etal (2010) unpublished.

Drug AloneDoes Not Facilitate

Hallam etal (2010) unpublished.

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

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