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Webinar Series Science Between Thought and Therapy: Translating Neurobiology Research into

Treatments 13 February, 2013

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Sponsored by:

Participating Experts:

Brought to you by the Science/AAAS Custom Publishing Office

Webinar Series Science Between Thought and Therapy: Translating Neurobiology Research into

Treatments 13 February, 2013

Ellen Sidransky, M.D.

National Human Genome Research Institute, NIH

Bethesda, MD

Anand Swaroop, Ph.D.

National Eye Institute, NIH

Bethesda, MD

Carlos A. Zarate, M.D.

National Institute of Mental Health, NIH

Bethesda, MD

Development of Rapid-Acting Antidepressants and Biomarkers of

Response

Carlos A. Zarate, Jr., M.D

Experimental Therapeutics & Pathophysiology Branch (ETPB)

Division of Intramural Research Program

National Institute of Mental Health

Major depressive disorders: a major cause of disability

>10% of the American population suffer from a mood disorder each year

Depression is one of THE leading causes of disability worldwide, ranking ahead of ischemic heart disease, cerebrovascular disease, cancers, infectious diseases, etc.

An increase in the death rate at any age, independent of suicide, smoking, or other risk factors

> 30,000 deaths from suicide/yr (cf ~ 18,000 homicides)

Individuals with major depression sometimes describe an emotional pain much worse than any physical pain that they have experienced

Drug Development in the past 50 years

Insel and Skolnick Mol Psychiatry 2006;11:11-17

# o

f M

ech

an

isti

call

y D

isti

nct

Dru

gs

Lithium

Anticonvulsants

Divalproex

Carbamazepine

Lamotrigine

Topiramate

Oxcarbazepine

Levetiracetam

Antipsychotics

Clozapine

Risperidone

Olanzapine

Quetiapine

Ziprasidone

Aripiprazole

Except for Li all available FDA approved treatments for BPD are anticonvulsants or Antipsychotic drugs

Antidepressants ONLY serotonin and

norepinephrine based (‘me too drugs’)

•Disruption to:

•Personal life

•Familial life

•Occupation

•Social life

•Increased economic

costs

•Risk for suicidal behavior

Natural course

Standard

antidepressant Treated course

Euthymic

Depressed

Manic Next generation antidepressant

6-12 months

10-14 weeks

33% remission

Hours/day

Identify a problem: Lag of onset of antidepressant effects

Course of

Illness

Targeting the Glutamatergic System to Develop Improved Therapeutics for Mood Disorders

Target

receptor

Brain region Effect

NMDA Hippocampus Reduced [3H]CGP-39653 and

MK-801 binding and reduced

levels of NR1 and NR2A

transcript

NMDA Sup temporal

cortex

NMDA receptor binding and NR1

subunit expression

NMDA ACC NR2A subunit decreased in

GABA interneurons

NMDA DLPFC Polymorphisms in genes coding

NR2B, no difference in mRNA

expression

AMPA Striatum Increased AMPA binding is

associated with decreased

GLUR1 subunit expression

AMPA DLPFC Decreased levels of GLUR2

Sanacora, Zarate, Krystal, Manji. Nat Rev Drug Discov 2008

Ketamine is a widely used

disassociate anesthetic mainly

for ambulatory surgery and

chronic pain

Ketamine is 10-50 times less

potent than PCP in blocking

Non-competitive NMDA receptor

antagonist

Psychotomimetic properties (5-

20%)

Abused as “club drug”

Modification in synaptic AMPA & NMDA receptors

Can the Onset of Action of Antidepressants be Accelerated?

Ketamine i.v. (0.5 mg/kg over 40 min)

Drug Free Period

2 weeks

Placebo Placebo

Ketamine Ketamine

1 week

Ratings: min: 0, 40, 80, 110, 230; Days: 1,2,3, 7, 14 (bipolar)

Study design 3 studies Unipolar and Bipolar Depression

Ketamine

Robust, rapid & relatively sustained antidepressant effects of low dose

ketamine, and response rates to ketamine in a double-blind placebo

crossover trial in patients with treatment-resistant major depression

Zarate et al. Arch Gen Psychiatry, 2006

13%

35

%

53% 56%

71%

58% 53

%

Response: 50% decrease in HAMD from baseline

62-

65%

35%

40 m 80 m

110 m 230 m

1 d 2 d

3 d 7 d

8 wks

Infusion

0

5

10

15

20

25

30

-60 40 80 110 230 Day 1 Day 2 Day 3 Day 7

Time (Minutes)

Ha

mil

ton

De

pre

ss

ion

Ra

tin

g S

ca

le

** **

*** *** ***

*

//

Ketamine Placebo Venlafaxine SSRI Bupropion

Infusion

33% remission day 1

5

10

15

20

25

30

-60 40 80 110 230 D1 D2 D3

HDRS

† ‡

// //

†

Minutes Days

D7

†

‡ ‡ Infusion

Unipolar depression

5

10

15

20

25

- 60 40 80 110 230 D1 D2 D3 D7 D10 D14

HDRS

†

† ‡

‡ ‡ ‡

‡

‡

Minutes Days

Bipolar depression

Rapid antidepressant response to ketamine in two different disorders

High SSI (>4) (n=10)

Low SSI (<3) (n=23)

-60 0 60 120 180 240 Minutes

0

2

4

6

8

10

12

]

]

]

]

]

]

]

]

]

]

d= 1.3

* * *

*

d= 2.4

Zarate et al. 2006; Diazgranados et al. 2010a; Diazgranados et al. 2010b

33% remission

Genes Gene expression Cellular Circuits Rapid reversal of complex

behavioral phenotype

Metabolome Neurochemical

Ketamine mGluR I gln

glu

glutaminase

glu

glu

mGluR I

EAAT3

Glu AMPA R

NMDA R (-)

KA R

Postsynapti

c neuron

Presynaptic neuron

gln

aketo

glutarate

TCA

Astrocyte

? AD

response

Moghaddam J Neurosci 1997

Time (min) Ket.

Inj.

-50

50

150

250

350

0 20 40 60 80 100

Saline Ketamine (10 mg/kg) Ketamine (20 mg/kg) Ketamine (30 mg/kg)

* *

*

* * * * * *

Ketamine increases glutamate release, thereby facilitating AMPA/NMDA throughput ---->mTOR activation----> Antidepressant effects

* p<0.05, ** p<0.01

*

*

**

* *

dose (mg/kg) 0 1 3 10

imm

ob

ile

tim

e (

se

c)

0

20

40

60

80

100

120

140

160

180 p=0.02

*

**

*p<0.05, **p<0.01

Ro 25-6981 in animal model of depression

0

20

40

60

80

100

120

140

160

180 p=0.01

Maeng et al. Biol Psych 2008

NR2B antagonist

(Ro256981)

24hs Antidepressant-like

Li et al. Science 2010

Genes Gene expression Cellular Circuits Rapid reversal of complex

behavioral phenotype

Metabolome Neurochemical

**

SAL KET NBQX KET+

NBQX

AMPA Antagonists block the

antidepressant effects of Ketamine

0

20

40

60

80

100

120

140

160

180

Glutamate Modulation in TRD: Pipeline (Partial List)

Compound

(Manufacturer)

Mechanism of

Action

Phase Route

MK-0657* (Merck)

NR2B Antagonist IIa p.o. Completed

CP101,606

(Pfizer)

NR2B antagonist IIa IV + response;

discontinued

RO4917523

(Roche)

mGluR5 allosteric

antagonist

IIa p.o. Ongoing study

AZD6765* (AstraZeneca)

NR2AB Antagonist IIb IV Completed

EVT 101

(Evotec)

NR2B antagonist IIa p.o. Study halted

AZD6765: A low-affinity NMDA channel blocker

AZD6765 was developed in Europe as an intravenous txt for

stroke but was not further pursued because of a lack of efficacy

AZD6765 is a low-trapping NMDA channel blocker, NMDA receptor

antagonist. It is blood-brain penetrant

AZD6765 well tolerated with dizziness, nausea, and vomiting,

being the most common AEs. No psychotomimetic effects up to

160 mg

Antidepressant effects in learned helplessness, FST

Anxiolytic activity in the rat punished responding model

0

5

10

15

20

25

30

35

40

-60 60 80 110 230Day1

Day2

Day3

MA

DR

S

Time (Minutes)

Placebo

AZD150

** *

0

5

10

15

20

25

HA

MD

(1

7 Ite

m)

Time (Minutes)

Placebo

AZD150

** * * * *

VEGF

Zarate et al. Biol Psych 2012

A double-blind placebo-controlled study of NMDA antagonist (AZD6765) in treatment-resistant depression (N=22)

Study of ketamine’s mechanism of action from synapses through a range of systems

Synaptic Plasticity

(mTOR, eEF2, GSK-3B inh)

•Glucose changes

(glutamate signal)

•Circuits/connectivity Cortical excitability

Genes Gene expression Cellular Circuits Rapid reversal of complex

behavioral phenotype

Polysomnograph

y MEG PET & MEG MRS

Neurochemicals

(Glx DM/DA-PFC

Glx/Glu ratio)

Synaptic Dysfunction

Medial prefrontal cortex layer V pyramidal

cells in brain-derived neurotrophic factor

Val66Met knock-in mice have both apical and

basilar dendritic atrophy

Antidepressant response to Ket in the

forced swim test is attenuated in brain-

derived neurotrophic factor Val66Met

knock-in mice

Liu et al. Biol Psychiatry 2012

Val66Met and Antidepressant Response to Ketamine

P = .025

Laje et al. Biol Psychiatry 2012

Salvadore et al., Biol Psychiatry 2010

Experiment 1 (an affective task):

rostral ACC activity is positively

correlated with AD response to

ketamine

MA

DR

S c

ha

ng

e s

co

re (

%)

R

L

Linear change in ACC activity

x=5

Rostral ACC

pretreatment

activity (Emotion)

Experiment 2 (a cognitive task): rostral

ACC activity is negatively correlated with

AD response to ketamine

Salvadore et al. Neuropsychopharmacology 2010

+1

-

+1

-

Rostral ACC

pretreatment

activity

(Cognition)

-20

0

20

40

60

80

100

-1.5 -0.5 0.5 1.5 2.5 3.5

-20

0

20

40

60

80

100

-1.5 -0.5 0.5 1.5 2.5 3.5

MA

DR

S c

han

ge s

co

re (

%))

1 1

+

MEG: Grand Averaged (N=20) Time-frequency plots

Baseline

40 Hz

RH stimulation

Left sensors LH stimulation

Right sensors

40

Hz

0 100 200 300 -100 100 200 300 -100 0

10

0

8

2

6

4

10

0

8

2

6

4

No

rma

lize

d P

ow

er

No

rma

lize

d P

ow

er

Baseline

stimulation

1.5

0.0

Lo

g1

0 No

rmaliz

ed

Po

wer

30-5

0H

z

Grand Averaged (N=20) Evoked Gamma-Band Source Analyses

Somatosensory

stimuli

Central sulcus

MEG: A sensory cortical signature of ketamine’s rapid antidepressant effects

Gamma rhythms are involved

in many aspects of cognitive

function from 1• sensory

representation through

selective attention and short-

term memory.

They possess the ability to

facilitate synchrony of neuronal

activity occurring in many,

anatomically distant areas at

the same time.

Using ketamine in rodents

produces an increase in gamma

rhythm generation

(frontoparietal, hippocampus).

Mean primary somatosensory cortical evoked gamma-band (30-50 Hz) response to

tactile stimulation for non-responders an responders before (pre) and 5-7 h after

ketamine administration (POST)

Contralateral (right) stimulation Ipsilateral (left) stimulation

Non-Responders (N=11) Responders (N=9)

Sti

mu

lus

-ev

oked

gam

ma

-ban

d r

esp

on

se p

ow

er

-1.0

-0.5

0.0

0.5

1.0

1.5

2.0

-1.0

-0.5

0.0

0.5

1.0

1.5

2.0

Baseline Post-

Ketamine

Diff Baseline Post-

Ketamine

Diff

*

*

**

**

*p < .05

**p < .01 Cornwell et al. Biol Psych 2012

Cells:

Ketamine enhances

AMPA:NMDA

throughput in critical

neuronal circuits and

activates the mTOR

pathway: increased

synaptic signaling

proteins and increased

number and function of

new spine synapses in

the PFC of rats

Systems:

ACC desynchronization

and functional

connectivity with the

amygdala during a

working memory task

predict rapid

antidepressant response

to ketamine

Behavior:

Rapid reversal

of Complex

Phenotype

Genes

Multiple susceptibility

alleles each of small

effect

? Ketamine effects

Cellular

Programming

Gene and

Protein

Expression

? Ketamine effects

The Neurobiology of Mood Disorders

Understanding the Mechanism of Ketamine Across Different Systems

5

10

15

20

25

30

-60 40 80 110 230 D1 D2 D3

HDRS

† ‡

// //

†

Minutes Days

D7

†

‡ ‡ Infusion

Depression

Genes Gene expression Cellular Circuits Rapid reversal of complex

behavioral phenotype

Metabolome Neurochemical

VAL/

VAL

MET+

BDNF SNP response

Conclusions

• The new paradigm of rapid antidepressant action is to develop antidepressant drugs that work in hours or a few days instead of weeks

• Scopolamine and ketamine are tools/models that can be used in understand the mechanisms involved & develop treatments with a rapid onset of action

• Directly targeting the muscarinic receptors and NMDA receptor complex may bring about rapid antidepressant effects in both unipolar and bipolar depression

• A more precise understanding of the downstream changes are relevant to the mechanism of rapid antidepressant action

• Anterior cingulate cortex activity modulation is associated with antidepressant response to ketamine

• Several bio-signatures appear promising and are associated with significant improvement in depressive sxs in patients treatment with scopolamine and ketamine

Research studies: http://patientinfo.nimh.nih.gov

1-877-MIND-NIH (1-877-646-3644)

email moodresearch@mail.nih.gov

zaratec@mail.nih.gov

Research = Hope

Sponsored by:

Participating Experts:

Brought to you by the Science/AAAS Custom Publishing Office

Webinar Series Science Between Thought and Therapy: Translating Neurobiology Research into

Treatments 13 February, 2013

Ellen Sidransky, M.D.

National Human Genome Research Institute, NIH

Bethesda, MD

Anand Swaroop, Ph.D.

National Eye Institute, NIH

Bethesda, MD

Carlos A. Zarate, M.D.

National Institute of Mental Health, NIH

Bethesda, MD

Detailed examination of

a single gene disorder Gaucher

Studies of rare recessive diseases may

provide a window into complex disorders

Ultimately help to unravel

complex disorders. Parkinson

Disease

Apply insights to other

monogenic disorders

PKU CF

Gaucher Disease

(GD) • Deficiency of enzyme

glucocerebrosidase,

accumulation of

glucosylceramide

• Variable age of onset

• Rare recessive, single gene

disorder

• Multi-organ involvement

• Symptoms include enlarged

spleens and livers, low platelet

counts, bone and brain

involvement

Parkinson Disease

(PD) • Loss of dopaminergic neurons

in the brain, accumulation of

Lewy bodies - aggregates of

proteins including α-synuclein

• Late onset

• Common disorder affecting 1.5%

of population over age 65,

complex multi-gene disorder

• Symptoms include bradykinesia,

rigidity and tremor, and

sometimes dementia

• Mainly affects substantia nigra

and brainstem

Clinical Studies

Cell Biology

Gaucher disease and parkinsonism

Gaucher disease Parkinsonism Integrated

translational

approach

Glucocerebroside + H20 Ceramide + Glucose

Glucocerebrosidase

Gaucher disease: A Mendelian lysosomal

storage disorder

C C CH2 O

C O

H H

OH

OH

N

CH2OH

OH

O

H

OH

O

Vast clinical heterogeneity is encountered

in this disorder

Type 1 Type 2 Type 3

Hydrops

fetalis

Asymptomatic

Congenital

ichthyosis Progressive

neurologic

degeneration Myoclonic

epilepsy

Parkinsonian

manifestations

Eye movement

disorder

2° neurologic

involvement

Skeletal

disease Visceral

disease

Neurologic

manifestations

Hydrocephalus, cardiac

valve calcifications

Gaucher disease: a spectrum of phenotypes

The association of glucocerebrosidase (GBA)

mutations and parkinsonism

This story began in the clinic, with rare patients with Gaucher disease who developed parkinsonism.

GD

PD PD also seen in relatives of Gaucher probands.

We and others noted an increased incidence of GBA mutations in patients with PD and LBD.

However many of the initial studies were greeted with skepticism due to limitations in power or controls and because GWAS did not identify GBA.

“The GBA example is an

illustration of how an

important genetic risk factor

for a complex disease can

evade detection by systematic

analysis: it only came onto the

radar because of astute

clinical observation.”

Rogaeva and Hardy,

Neurology - June 10, 2008

Editorial

This association has persisted!

0

50

100

150

200

250

1998 2001 2004 2007 2010 2012

# Publications on GCase and PD

GBA is now the most common genetic

risk factor for PD.

However the VAST majority of patients with GD

and GBA mutation carriers never develop PD!

International multi-center study of GBA

mutations in PD

Subjects with PD are >5 times

more likely to have a mutation

in GBA (Overall OR=5.43;

95%Cl=3.89-7.57)

GBA carriers had earlier PD

onset and more cognitive

deficits.

Oct 2009

16 centers joined,

5691 genotypes from

patients with PD and

>5000 from controls

Significant association found.

Odds ratio = 8.28 (95%CI = 4.78 - 14.88).

Mutations in GBA likely play an even

larger role in DLB than PD!

(JAMA Neuro; IN PRESS)

Multicenter analysis of GBA in dementia with Lewy bodies (DLB)

11 centers, 721 cases with DLB, 1962

controls.

1. To study F-dopa uptake and

evaluate PET as a surrogate marker

in subjects with GBA mutations

2. To establish earliest signs of PD in

at-risk subjects

Clinical features and PET imaging in subjects

with GBA mutations (Collaboration: K Berman, NIMH)

Clinical Studies

Physical exam

Neurologic exam (UPDRS)

Neurocognitive evaluation

Olfactory testing

Screens for non-motor

symptoms

Imaging Studies

MRI (structural abnormalities)

F-18 Dopa PET (L-Dopa

metabolism)

15-H2O PET (cerebral blood

flow)

Trans-cranial sonogram (TCS)

(midbrain structures)

Goals:

Included: GD patients and carriers

with +FH of PD

GD/PD

First 40 studies

published in Brain,

2012

Formation of insoluble a-

synuclein aggregates

Neuronal

cell death

Mutant

glucocerebrosidase

may lead to…

Increased

aggregate

formation

Organelle

dysfunction:

decreased

aggregate

clearance

How can mutations in a metabolic enzyme

lead to parkinsonism?

Gain-of-function:

a-synuclein

aggregates

Neuronal

cell death

Mutant

glucocerebrosidase

may lead to…

How can mutations in a metabolic enzyme

lead to parkinsonism?

Unstable or deficient

protein

Degradation

Insufficient enzyme

GlcCer accumulation

Neuronal cell death

Loss-of-function:

soluble α-syn

oligomers and fibrils

α-syn oligomers block ER-

Golgi trafficking of GCase (Mazzulli et al. Cell, 2011)

“Bidirectional

feedback loop”

Shown by fluorescence spectroscopy, NMR and co-

immunoprecipitation studies, but only at pH 5.5.

Interaction occurs at C-terminus of α-synuclein.

A molecular link between α-syn and glucocerebrosidase Collaboration with J. Lee, NHLBI (JBC 2011)

A B

This binding at lysosomal pH could facilitate α-syn

degradation or prevent aggregation. The GBA story

implicates the lysosome in PD pathogenesis.

Chemical chaperone therapy for Gaucher disease

Chemical chaperones may partially correct the enzyme deficiency.

High Throughput Screening Collaboration: W. Zheng, J. Maragun and C. Austin

Small molecule therapy may stabilize mutant

GCase and be used to treat GD as well as PD

GCase chaperones as therapy for GD

New screening approach: (Goldin et al.PLoS One 2012)

Patient spleen sample = source of mutant GCase.

HT screen - 250K compounds.

30 new non-inhibitor chaperones identified.

Leads improved translocation in patient fibroblasts.

In macrophages: compounds reverses storage!

•Embryoid bodies generated from Gaucher fibroblasts

•Cells show appropriate markers,karyotype; form teratomas .

•Differentiated into monocytes and then macrophages.

•iPSC derived Gaucher macrophages show storage!

•Model useful for drug development and understanding

pathophysiology.

iPS cells from

type 2 GD DAPI Bodipy-GlcCer

Control Gaucher type 2

Progress with Gaucher iPS cells

hiPSC –derived macrophages

(fed with labeleds erythrocyte ghosts)

Lead chaperone decreases storage in both

N370S/N370S macrophages and iPSC-

macrophages (IVS2+1/L444P)

Cultured

control

macrophages

Gaucher iPSc-

macrophages

Cultured

Gaucher

macrophages

Testing of lead compound in macrophage

models of Gaucher disease

Understanding the links between the two

disorders

Gaucher

Disease Parkinsonism

Pathogenesis of

both disorders

Lysosome

Genetic

counseling

Therapeutic

strategies

Acknowledgements Section on Molecular Neurogenetics

Arash Velayati Ozlem Goker-Alpan

Behafta Berhe Barbara Stubblefield

Wendy Westbroek Rafi Tamargo

Elma Aflaki Grisel Lopez

Nahid Tayebi Ann Marie Gustafson

Emerson Maniwang Ehud Goldin

Collaborators

Ari Zimran-Jerusalem Mark Cookson- NIA

Jennifer Lee- NHLBI Andy Singleton- NIA

Wei Zheng- NCAT Mark Hallett- NINDS

Benoit Giasson- U. Florida Ricardo Feldman UMD

Raphael Schiffmann- Baylor Edward Ginns- U. Mass.

Richard Youle- NINDS Karen Berman- NIMH

Joe Masdeu- NIMH Glenda Halliday- Australia

Juan Marugan -NCAT Scott Martin-NCAT

Dimitri Krainc-Harvard

With special thanks to the patients, family members and referring

physicians who have contributed greatly to these studies.

Sponsored by:

Participating Experts:

Brought to you by the Science/AAAS Custom Publishing Office

Webinar Series Science Between Thought and Therapy: Translating Neurobiology Research into

Treatments 13 February, 2013

Ellen Sidransky, M.D.

National Human Genome Research Institute, NIH

Bethesda, MD

Anand Swaroop, Ph.D.

National Eye Institute, NIH

Bethesda, MD

Carlos A. Zarate, M.D.

National Institute of Mental Health, NIH

Bethesda, MD

Anand Swaroop, Ph.D. Senior Investigator and Chief,

Neurobiology-Neurodegeneration & Repair Laboratory National Eye Institute, National Institutes of Health

Capture, Integrate, Process, Submit visual information Over 30% of our brain devoted to visual processing, even larger devoted to follow up

A major cause of untreatable blindness

Clinically and genetically heterogeneous

Over 200 genetic loci for Mendelian

diseases; 150+ genes

Many genes – same phenotype; Same

gene/mutation – different phenotypes

Numerous syndromic diseases

Multifactorial diseases – age-related

macular degeneration, diabetic

retinopathy, glaucoma: susceptibility

genes, environment

The dysfunction or death of photoreceptors leads to vision loss

Rods (dim light) and Cones (bright light, color vision) – 20:1 in humans

S, M, L cones in humans. Only S and M cones in mice

Highly metabolically active. Outer segments regenerated in 10 days

Aging Disease

Treatment

Development

birthdating in mouse retina (Cepko 1996)

All cells generated from common pool(s) of retinal progenitor cells (RPCs)

Conserved order of birth in all vertebrates. Rods are almost 70% in mouse,

born over an extended period. Most cones born prenatally. Peak of rod birth P0-P2

Swaroop et al. Nat Rev Neurosci 2010

No rods differentiate in the absence of Nrl – cone only

retina, S-cone characteristics (Mears et al. Nat. Genet. 2001)

ko wild type

Dark-adapted ERG

-2.4

-1.4

0.6

0.1

Light-adapted ERG

500 µV

100 ms

Sti

mu

lus

In

ten

sit

y (

log

cd

-s/m

2)

Wild-type Nrl-ko

Window of developmental plasticity

Crx promoter – Nrl: all rods

S-opsin promoter – Nrl: 40% rods Oh, E et al. (2007) PNAS 104, 1679-1684

Ng L et al. J. Neurosci. 2011;31:11118-11125

Swaroop et al. Nat Rev Neurosci 2010

Combinatorial action of multiple factors

S-cone “default”

NRL and TRb2 dictate the generation of three photoreceptor types

NRL action is dominant over TRb2

M. Akimoto et al. (2006) PNAS 103, 3890

Gene Regulatory Networks underlying development and disease Cell Replacement Therapy Drug Discovery

Cell-type specific gene expression

maturation

functional photoreceptor

immature photoreceptor

Elaboration of outer segments and synapse formation

immature photoreceptor

post-mitotic precursors

E12-E18 P0-P2 P4-P6 P8-P12 P21-P28

mRNA profiling of flow-sorted rods – Affy GeneChips and RNA-Seq

(Matthew Brooks, Linn Gieser, Jerome Roger, Norimoto Gotoh, Tiziana Cogliati)

Transcription factors – ChIP-Seq (Hong Hao et al. PLoS Genet 2012) and Protein

complexes (Sharda Yadav)

Histone modifications – ChIP-Seq (Hyun-Jin Yang)

DNA methylation (Jung-Woong Kim)

Differentiation and integration of GFP-tagged rod precursors

only immature developing rods

MacLaren et al. Nature 2006

Yao, Zacks et al., IOVS 2009

Homma et al. Stem Cells, 2013 in press

Crx-ko mouse retina

Immature Photoreceptors

Cell replacement Disease mechanisms

Small molecule screening

hES cells

Induced pluripotent stem (iPS) cells

iPS cells from genetically abnormal cells – patients

Eiraku et al. 2011 Y. Sasai group

Optic Vesicle

Kohei Homma and Jessica Cooke

Dnmt1 knockdown in early eye development Nasonkin et al. Development 2013 in press

Photoreceptors from stem cells – more work is needed on

function, quality, growth characteristics, epigenome

No cell surface markers yet for distinct stages of differentiation

Cell transplantation methods – good

Cell spreading – scaffold may be needed

Cell integration – poor

Synapse formation?

Cell survival – for several months

Better assessment of efficacy in animal models – Optical

coherence tomography, optokinetic response……

Integration with RPE: 3-D reconstruction

Douglas Forrest (NIDDK), Mahendra Rao (NCRM),

Robert Fariss, Lijin Dong, Kapil Bharti and Sheldon Miller (NEI)

N-NRL 2012

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Webinar Series Science Between Thought and Therapy: Translating Neurobiology Research into

Treatments 13 February, 2013

Ellen Sidransky, M.D.

National Human Genome Research Institute, NIH

Bethesda, MD

Anand Swaroop, Ph.D.

National Eye Institute, NIH

Bethesda, MD

Carlos A. Zarate, M.D.

National Institute of Mental Health, NIH

Bethesda, MD

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Webinar Series Science Between Thought and Therapy: Translating Neurobiology Research into

Treatments 13 February, 2013