MouseAge slideshare

Know Your Models!(Know your Disease)

Multiple Sclerosis Models &Experience with Clinical Translation

MouseAGE 2015

Prof. David [email protected]

Slides Available on www.ms-res.org

(Slideshare)

MOUSEAGE 2015

• KNOW YOUR DISEASE-DESCRIPTION OF MULTIPLE SCLEROSIS

• KNOW YOUR MODEL- DESCRIPTION OF MS MODELS

• KNOW THE LIMITATIONS: FAILURE TO TRANSLATE

• LIMIT YOUR LIMITATIONS: ARRIVE REPORTING GUIDELINES

• DRUG DEVELOPMENT: BENCH TO BEDSIDE

Slides Available on www.ms-res.org

(Slideshare)

Multiple sclerosis (MS) is a chronic (auto)immune-mediated CNS-confined demyelinating disease affecting 2,500,000 people worldwide

(Restricted Distribution: Northern European Dissent)

Disease onset is usually between 20 and 40 years of age (F:M ratio, 2:1. Polygenic-150 genes identified so far)

(30% concordance in Identical Twins, 100% Infected with EBV)

MS is clinically characterized by a relapsing-remitting course usually followed by a progressive phase

MS is pathologically heterogeneous – inflammation, demyelination and neurodegeneration (axonal loss and neuronal damage)

Spontaneous repair occurs but MS invariably progresses (ambulatory problems in 70-80% patients at 25 years from onset)

KNOW YOUR DISEASE-BIOLOGY OF MS

NERVE LOSS

PROGRESSIVE MSRELAPSING-REMITTING MS

DISABILITY

Frequent inflammation, demyelination,axonal transections, plasticity and remyelination

Inflammation, Persistent Demyelination & Gliosis

Infrequent inflammation, Gliosis, Chronic Neurodegeneration

CLINICAL THRESHOLD

INFLAMMATION

Symptoms

Clinical Effects are Due to Altered Nerve Conduction

CLINICAL COURSE

Immune-MediatedBeta-interferons, Alemtuzumab (CD52),

Cladribine, Bone Marrow Transplantation, Fingolimod (S1P1-modulator) , Rituximab

(CD20) are ACTIVE

NeurodegenerationBeta-interferon, Alemtuzumab,

Cladribine, RituximabBone Marrow Transplantation,

Fingolimod are INACTIVE


Eyes,Brain & Spinal Cord

You are told you have Eyes,Brain & Spinal Cord

You are told you have

White Blood Cells

No Repair

• INFLAMMATORY, DEMYELINATING, NEURODEGENERATIVE DISEASE OF CNS

•MULTIFOCAL OLIGODENDROCYTE LOSS

MS plaques


Myelin (blue)stain

NORMAL AGINGATROPHY RATE 0.1% p.a.

MULTIPLE SCLEROSISATROPHY RATE 0.4-1.0 %

MS is a Neurodegenerative Disease


Brain atrophy occurs across all stages of the disease

De Stefano, et al. Neurology 2010

n= 963 pwMS


ATROPHY


Onset of Progressive MS is Age-Sensitive andIndependent of Pre-Progression Disease Course

Confavreaux et al. 2006, Tutuncu et al. 2012

0 10 20 30 40 50 60 70 80

100

80

60

40

20

0

PPMS

SPMS

0 10 20 30 40 50 60 70 80

100

80

60

40

20

0

PPMS

SPMS

Mean Age at MS Onset (Years) Mean Age at PMS Onset (Years)

Per

cen

tag

e

Per

cen

tag

e


in vitro

monkeys

rodents

clinic

Mechanisms of Disease Design of Therapies Safety & Ethics

monkeys

clinic

discovery/screening

Validation/safety

safety/ preclinical

clinical trials

KNOW YOUR DISEASE-BIOLOGY OF MS MODEL-WHY USE ANIMALS?

MS was called an Autoimmune, Demyelinating Disease of the White Matter

MYELIN = BROWN

DEMYELINATION

MONONUCLEAR CELLINFILTRATE

BLOOD VESSEL(VENULE)

KNOW YOUR DISEASE-BIOLOGY OF MS/MODEL-BIOLOGY OF MS


CHEMICAL-INDUCED DEMYELINATION

VIRAL-INDUCED DEMYELINATION

AUTOIMMUNE-INDUCED DEMYELINATION

EXPERIMENTAL AUTOIMMUNEENCEPHALOMYELITIS (EAE)

IN MAMMALS(MYELIN-REACTIVE AUTOIMMUNITY)

SEMLIKI FOREST VIRUSMOUSE HEPATITIS VIRUS(NEUROTROPHIC VIRUS)

CUPRIZONE FEEDINGLYSOLECITHIN INJECTION

(OLIGODENDROCYTE TOXIN)

MONONUCLEAR CELL INFILTRATE

TRANSGENE-INDUCED DEMYELINATION

NO ANIMAL GETS SPONTANEOUS MS-LIKE DISEASE


Myelin Neurofilament

Demyelination

AxonalTransection

Axonal Transections are Associated with Inflammation

Control White Matter <1transection/mm2

Core of Chronic Lesion 875transection/mm2

Edge of Chronic Active Lesion ~3000transection/mm2

Active Lesion ~11000transection/mm2



AUTOIMMUNE-INDUCED DEMYELINATION

EXPERIMENTAL AUTOIMMUNEENCEPHALOMYELITIS (EAE)

IN MAMMALS(MYELIN-REACTIVE AUTOIMMUNITY)

MONONUCLEAR CELL INFILTRATE

Grey Matter Demyelination

Grey Matter Lesions have few T cells & macrophages

Experimental Autoimmune Encephalomyelitis

1. Active EAE - induced with myelin proteins or

peptides in CompleteFreund’s Adjuvant.

Myelin proteins in CFA

2. Adoptive EAE - induced by T cell transfer from mice immunised for active EAE.

T cells to myelin proteins

Myelin proteins in CFA

3. Myelin TCR Transgenic - Develop Spontaneous EAE.

KNOW YOUR MODEL-BIOLOGY OF EAE

No Clinical Disease-No Spinal Cord Infiltration- No Cytokine X, Y or Z Limp tail

Impaired righting

reflex

hindlimb paralysis

Moribund

partial paralysis

Normal

Remission

0

1

2

3

4

5

(1)

Clinical Score

Day 7

Spinal cord homogenate in Freund’s complete adjuvant

Day 0

Spasticity & TremorsDevelop


Video is Coming Next

43

No Clinical Disease-No Spinal Cord Infiltration- No Cytokine X, Y or Z Limp tail

Impaired righting

reflex

hindlimb paralysis

Moribund

partial paralysis

Normal

Remission

0

1

2

3

4

5

(1)

Clinical Score

Day 7

Spinal cord homogenate in Freund’s complete adjuvant

Day 0

Spasticity & TremorsDevelop



43

MULTIPLE SCLEROSIS MODELS


Time Post-Induction (Days)

10 15 20 25 30 35 40

Mea

n N

euro

logi

cal S

core

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

Acute (ABH, SJL) EAE

NerveLoss

Chronic (C57BL/6) EAE

TailParalysis

HindLimbParalysis



ConductionBlock

Strain Antigen

C57BL/6 MOG35-55

ABH PLP56-70

ABH MOG8-22

ABH MOG35-55

PL/J MBP1-9

SJL MBP89-101

SJL PLP139-151

SJL PLP178-191

MOG Myelin oligodendrocyte glycoprotein, MBP Myelin Basic Protein, PLP Proteolipid Protein

Normal Remission 1

Remission 2 Remission 4

NfH

(µ

g/m

g t

ota

l p

rote

in)

Number of AttacksN RM1 RM2 RM3

50

100

150

200

250

300

350

400Axonal Content Assessed By Neurofilament ELISA

www.msbrainhealth.org

No-evidence of Disease Activity (NEDA)


Stop Relapses Save Brain

Leg moved to full

flexion forassessment

Spastic Leg

RE

SIS

TA

NC

E F

OR

CE

TO

HIN

DLI

MB

FL

EX

ION

(N

)

0.00

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.40

0.45

Left leg Left legLeft legRight Leg Right Leg Right Leg

Non-spastic

Remission

Paralysed

Relapse

Spastic

Remission

0.08 ± 0.01# 0.03 ± 0.01* 0.17 ± 0.10 *,#

SYMPTOMATIC MODELS OF MS

Chronic EAE RM4(6 months )

Normal

Post Relapse-Remission

Spastic Limbs

Bladder Problems


PERIPHERAL IMMUNITY Slow RELAPSE RATE

NEURODEGENERATION Slow PROGRESSION

SYMPTOM CONTROL Improve QUALITY OF LIFE

REPAIR Reverse Deficits

OUTCOME OF CONTROLDISEASE PROCESS

Increasing Number of Effective Drugs

Effective Drugs with Unpleasant Side-Effects

No Treatments

No Treatments

Adaptive Immune –Dependent InflammationAdaptive Immune–Independent, Innate Dependent

Recently DemyelinatedChronic Demyelinated/Gliotic Lesions


• PRE-CLINICAL FAILURE• Model does not reflect human disease biology• Drug does not target biology relevant to human application• Lack of appreciation of human disease• Dogma & overstating effect • Model used in a way that does not reflect human indication• Drug doses are not used in at physiological doses• Drugs are not delivered in a way appropriate to how used in humans• Studies are not transparent & not reproducible (Ineffective Study Design)• CLINICAL FAILURE • Lack of clear understanding of human pathology• Drug is seldom investigated by scientists developing the Idea.• Over-interpretation of significance of pre-clinical studies• Drug is not used at a dose relevant to the pre-clinical studies• Population does not respond as predicted. (Ineffective Trial Design)• Dose-limiting side-effects• Study Underpowered, too short or unrealistic expectations• Measurement Instruments Inadequate Clinical Outcomes and Surrogate Markers• Wrong Group of pwMS studied (IneffectiveTrial Design)• Commercial Interests

Mechanism is all Important.

Relevance of Slight Delay of a Few Days, Slight Diminution

Prophylactic/Therapy

“Toxicity leading to Stress”

“Route & Timing”Reporting Issues

KNOW THE LIMITATIONS-FAILURE TO TRANSLATE

Two thousand drugs tested in EAE, only nine-ten classes of drugs approved

Time Post Induction (Days)

10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25

Mean

Clin

ica

l Sco

re

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0Vehicle n= 10/10Test Drug n = 10/10 Test Drug 2 n=0/10

or n = 7/10

ARRIVE Guidelines (UK)Kilkenny C, Browne WJ, Cuthill IC, Emerson M & Altman DG. Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research. PLoS Biol. 2010; 8(6):e1000412 (2010)

National Research Council (USA). Institute for Laboratory Animal Research. Guidance for the Description of Animal Research in Scientific Publications. National Academies Press, Washington (DC) (2011).

Guidelines on EAE StudiesBaker D, Amor S. Publication guidelines for refereeing and reporting on animal use in experimental autoimmune encephalomyelitis. J Neuroimmunol. 2012 242:78-83

LIMIT YOUR LIMITATIONS-EXPERIMENTAL DESIGN

RANDOMISATION

BLINDING

SAMPLE-SIZE

DATA HANDLING

REPLICATION

NINDS GUIDELINE Nature 2012; 490:187

>10%

>20%

>1%

ARRIVE Guidelines (UK)Kilkenny C, Browne WJ, Cuthill IC, Emerson M & Altman DG. Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research. PLoS Biol. 2010; 8(6):e1000412 (2010)

National Research Council (USA). Institute for Laboratory Animal Research. Guidance for the Description of Animal Research in Scientific Publications. National Academies Press, Washington (DC) (2011).

Guidelines on EAE StudiesBaker D, Amor S. Publication guidelines for refereeing and reporting on animal use in experimental autoimmune encephalomyelitis. J Neuroimmunol. 2012 242:78-83


RANDOMISATION

BLINDING

SAMPLE-SIZE

DATA HANDLING

REPLICATION

NINDS GUIDELINE Nature 2012; 490:187

>10%

>20%

>1%

Parametric(47%)t- test(46%)

NonParametric

39%Not

Reported(14%)

Parametric(65%)

t test (67%)

Non-Parametric (4%)

NotReported

(31%)

All EAE Publications 6 months 1:12:2011-31:5:2012 n=175

All EAE Publications 2 Years1:1:2010-11:9:2012 n=26

All PUBMED PUBLICATIONS

BIG 6 PUBLICATIONSNature, Nat Med, Nat Immunol,

Nat. Neurosci, Science, Cell

T-test CriteriaContinuousNormally DistributedEqual Variances


Figure legend. Clinical scores of two independent EAE experiments at d23 post disease induction. Individual scores as well as the mean score of two independent experiments are shown. Control: n=10, vehicle: n=13, xxxxx-345: n=11. Control versus vehicle: P=0.620, control versus xxxxx-345: P=0.017, vehicle versus xxxxx-345 P=0.029. * indicate P values <0.05 and ** indicate P values <0.005 based on a non-paired Student’s t test. Error bars are s.e.m

Nature Paper 2015

Drug-treated animals the scores appear to be: 0, 0 ,0, 0.5, 0.5, 2, 2.5, 3, 3.5, 3.5, 3.5 n=11 Vehicle scores appear to be: 0.5, 2.5, 2.5, 2.5, 2,75, 2.75, 3, 3.5, 3.5, 3.5, 3.5, 3.5, 3.5 n=13.Do a t test drug verses vehicle p=0.029

The assumptions of a t test (a) Data is normally distributed. You test this and it passes the test p=0.152,

(b) data groups have equal variances Test for that and it fails P<0.05. (c) Data is Parametric. Fail. It is non-parametric.

t test is not a valid testMann Whitney test. P=0.082.........Ooooops.


• PRE-CLINICAL FAILURE• Model does not reflect human disease biology• Drug does not target biology relevant to human application• Lack of appreciation of human disease• Dogma & overstating effect • Model used in a way that does not reflect human indication• Drug doses are not used in at physiological doses• Drugs are not delivered in a way appropriate to how used in humans• Studies are not transparent & not reproducible (Ineffective Study Design)• CLINICAL FAILURE • Lack of clear understanding of human pathology• Drug is seldom investigated by scientists developing the Idea.• Over-interpretation of significance of pre-clinical studies• Drug is not used at a dose relevant to the pre-clinical studies• Population does not respond as predicted. (Ineffective Trial Design)• Dose-limiting side-effects• Study Underpowered, too short or unrealistic expectations• Measurement Instruments Inadequate Clinical Outcomes and Surrogate Markers• Wrong Group of pwMS studied (IneffectiveTrial Design)• Commercial Interests

Mechanism is all Important.

Relevance of Slight Delay of a Few Days, Slight Diminution

Prophylactic/Therapy

“Building Site Effect”

“Route & Timing”

“Placebo Effect”

Less Circuitry so Less Compensation Capacity

Non-Responders

Immune (T/B cell) or NeurodegenerationProfessional Trialists

Reporting Issues

Two thousand drugs tested only nine-ten classes of drugs approved



Once Drugs Become Available, Clinicians Voice their Opinion that Animal Experiments are not worth while, because of the failures

“It is now possible to conduct a Phase II trial for anti-inflammatory MS drug candidates within a few months…..it is not useful to pre-screen potentially effective drugs using the EAE model (Ransohoff 2006)”_______________________________________________________________________________________

EAE MS____________________________________________________________________________________________________MS DRUGSCopaxone Inhibition InhibitionBeta Interferon Inhibition InhibitionCD49d-specific mAb Inhibition InhibitionGilenya/Fingolimod Inhibition InhibitionAubagio/teriflunomide Inhibition InhibitionTecfidera/Dimethy Fumarate Inhibition InhibitionCD52-specific mAb Inhibition Inhibition(CD20-specific mAb) Inhibition Inhibition

/Context Dependent /Context Dependent /Worsening

/No effect/Worsening

FAILURESCD25-specific mAb Worsening InhibitionGamma Interferon Inhibition WorseningTNF-specific mAb Inhibition WorseningPDE4 inhibitor (rolipram) Inhibition No Effect/WorseningAntigen-Specific Treatments Inhibition No Effect/WorseningTh2 Cytokines (IL-4/IL-10) Inhibition No EffectCD4-specific mAb Inhibition No EffectIL-12/23-specific mAb Inhibition No Effect____________________________________________________________________________________________________

Treg cells important

Th1/Th17 cells important

If 65% T cell Depletion does not Stop EAE, Why would it be expected to stop MS?

The Trial in MS was doomed before it even started?

ACUTE EAE

IL-12/23 KO C57BL/6 EAE non-susceptible (IL12p40 + IL12p35 = IL-12)anti-IL23 (p40) C57BL/6 EAE inhibited (IL-12p40 + IL23p19 = IL-23)anti-IL23 (p40) ABH EAE inhibited

RELAPSING EAEanti-IL-23 (p40) ABH No inhibitory effect (Heremanns et al. 1999)

RELAPSING MSanti-IL23(p40) Human MS No inhibitory effect

Th17

IL-23IL-6/TGFb

Th1

IL-12

Th2

IL-4

B

IL-4, IL10, IL-13 IFNg

IL-4IL-10IL-13

IL-17IL-21IL-22

IFN-g

Ustekinumab(Segal et al 2008)


Time Post-inoculation (Days)

0 7 14 21 28 35 42 49 56 63 70 77Dev

elo

pm

ent

of

Clin

ical

EA

E (

%)

0

10

20

30

40

50

60

70

80

90

100

Untreated

CD4b mAb 3 weeks

CD4d&CD8d mAb D12 + CD4b mAb 3 Wks

“Anti-CD4 antibody Cures EAE”


Time Post-inoculation (Days)

0 7 14 21 28 35 42 49 56 63 70 77Dev

elo

pm

ent

of

Clin

ical

EA

E (

%)

0

10

20

30

40

50

60

70

80

90

100

Untreated

CD4b mAb 3 weeks

CD4d&CD8d mAb D12 + CD4b mAb 3 Wks

Anti-CD4 antibody Causes Transient Immunosuppression in EAE


• CD4 T cell depletion inhibits EAE

• CD4 T cell deletion inhibits virtually every T and B Cell mediated autoimmunity

• CD4 T cell deletion does not inhibit multiple sclerosis (Lindsey et al. 1994 Neurol 44:413 : 810; van Oosten et al. 1998 Mut Scler 1:339)

.

• CD4 T cell deletion does not inhibit other human autoimmune diseases

Problem with the StudyPlanned <60% DepletionNaïve CD45RA preferentially affectedPrimed CD45RO T cells relatively unaffected (Llewellyn-Smith et al. 1997 Neurol 48:810; 48)

MS IS NOT CONTROLLED BY T CELL DEPLETION

No effect on Gadolinium enhancing lesions

If 60% T cell Depletion does not Stop EAE, Why would it be expected to stop MS?

The CD4 trial in MS was Probably doomed before it even started


Degree of CD4 depletion was important with regard to treatment efficacy.There was a significant 41% reduction in relapses.

Red = abundant CB1 receptors Black = moderately abundant CB1 receptors

PHARMACEUTICAL CANNABIS

BENCH TO BESIDE – SYMPTOM CONTROL

Time Post-Injection (Min)

0 10 20 30 40 50 60 70 80 90 100 110 120

Cha

nge

in H

indl

imb

Stif

fnes

s (%

) ±

SE

M

-50

-40

-30

-20

-10

0

10

20

Sativex Vehicle

Red = abundant CB1 receptors Black = moderately abundant CB1 receptorsBENCH TO BESIDE – NEUROPROTECTION OR NOT

Placebos did not progress as predicted

Zajicek J et al. 2013

P<0.01

CUPID Cannabinoid Use in Progressive Inflammatory brain Disease.

Animal Studies show that Cannabinoids are Neuroprotective

Compounds in cannabisTHC & CBD causeNeuroprotection

Cannabis Receptor LossCB1 KO exhibitNeurodegeneration

Natural Ligand IncreaseFAAH KO loosesNeuroprotection

FAAH inhibitorsNeuroprotection

Red = abundant CB1 receptors Black = moderately abundant CB1 receptorsBENCH TO BESIDE – NEUROPROTECTION OR NOT

Placebos did not progress as predicted

Zajicek J et al. 2013

P<0.01

Ambulatory PeopleStarting EDSS less than 5.5

CUPID Cannabinoid Use in Progressive Inflammatory brain Disease.

Animal Studies show that Cannabinoids are Neuroprotective

Compounds in cannabisTHC & CBD causeNeuroprotection

Cannabis Receptor LossCB1 KO exhibitNeurodegeneration

Natural Ligand IncreaseFAAH KO loosesNeuroprotection

FAAH inhibitorsNeuroprotection

INFLAMMATORY PENUMBAAnimal Studies indicate that sodium channel blockers can be neuroprotective by: •Inhibiting metabolic overload in nerves •Blocking microglial activity

Lamotrigine trial in secondary progressive MS fails Brain atrophy MRI shows (pseudo) atrophy greater than placebo. Drug was poorly tolerated (Kapoor et al. 2010).

50% of people in trial are not drug compliant.Neurofilament Biomarker is reduced in DrugCompliant individuals (Gnanapavan et al. 2013)

Animal studies show that sodium channel blockers are particularly active during the inflammatory penumbra. (Al-Izki et al. 2014)

PLP (brown) myelin Stain)

Red = abundant CB1 receptors Black = moderately abundant CB1 receptorsBENCH TO BESIDE – NEUROPROTECTION

Optic Neuritis isOften First Sign of MS

Most accessible part of Human CNS

Courtesy of Roy Weller


EYE

OPTIC NERVE

VISUALCORTEX

The eye is the window to the brain…

OCCIPITALLOBE

The Visual SystemX

Damage in MS

Optic NeuritisCommon First

Sign of MS

Occurs in Over50% of MS

X


EYE

OPTIC NERVE

VISUALCORTEX

The eye is the window to the brain…

OCCIPITALLOBE

The Visual SystemX

Damage in MS

Optic NeuritisCommon First

Sign of MS

Occurs in Over50% of MS

X



C57BL/6-Tg(Tcra2D2,Tcrb2D2)1Kuch /J


C57BL/6-Tg(Thy1-CFP)23Jrs /J

Develops Spontaneous/Induced Optic Neuritis.Subclinical Spinal Cord DiseaseLess Severe than Classical EAE

Fluorescent RGC Detection of Nerve Loss in Living Eye

Repeated Monitoring Not Requiring Histology

Disease is Concentrated in the Visual SystemHuman Relevant Outcome Measures


C57BL/6-Tg(Tcra2D2,Tcrb2D2)1Kuch.Cg-Tg(Thy1-CFP)23Jrs /J = FLASH GORDON

Low Contrast Eye Chart

Human Test

Visual acuity is a measure of clearness of vision and is used as a measure as to how you can see

Mouse Test

Visual tracking drum

Net

pos

itive

hea

d m

ovem

ents

0

2

4

6

8

10

12

14

Before Optic

Neuritis

AfterOptic

Neuritis

Loss of vision

Head movementsare Reduced after

Optic Neuritis(Nerve Loss)


MEASURING SIGHT-VISUAL ACUITY

Reference electrode

Recording electrode

Heating pad

Visual Evoked Potential (VEP)

Z ZZ

Electrophysiology can be used to measure the Visual Evoked Potential (VEP). This

is a measure of the neurotransmission from the

eye to the visual cortex.

Human Test

Mouse Test

Latency

Latency of VEPis Increased after

Optic Neuritis(Demyelination)

BeforeOptic

Neuritis

AfterOptic

Neuritis

Loss ofNerve

Conduction

Amplitude

Amplitude of VEPis Reduced after

Optic Neuritis(Nerve Loss)

Ampli

tude

(µV)

0

10

20

30

40

BeforeOptic

Neuritis

AfterOptic

Neuritis

Loss of vision


MEASURING SIGHT-ELECTROPHYSIOLOGY

Optic Nerve HeadGanglion CellLayer (GCL)

OCT is a non-invasive retinal imaging tool to look at the structure of the retina.

Human Test Mouse Test

Optic Nerve Head

OCT imageHistology image

Eye from Living AnimalEye from Dead Animal

OuterNuclear Layer

Photo-Receptors

Ganglion Cell Layer

Inner Nuclear Layer


OPTICAL COHERENCE TOMOGRAPHY (OCT)

Before Induction

After Induction

Optic Nerve Head

Optic Nerve Head

OCT scan

OCT Can Detect Loss of RGC in Mouse with Optic Neuritis


OPTICAL COHERENCE TOMOGRAPHY (OCT)

cSLO is a high resolution retinal imaging tool to look at the structure of the retina

Optic NeuritisPre-Disease

After Disease Onset

Retinal Ganglion Cell Loss

Before Disease Onset

Retinal Ganglion Cell Loss

cSLO Image

BloodVessel

Optic Nerve Head

Retinal GanglionCell

Optic Nerve Head

Pre-Disease 2018 cells/mm2

Optic Neuritis 285 cells/mm2

RGCLoss

P<0.001


Confocal SCANNING LASER OPHTHALMOSCOPY (cSLO)

Day 0 2 10 14 21

Demyelinating mAb(250μg Z12 mAb i.p.)

Disease Induction (150ng Pertussis Toxin i.p.)

T cell-Mediated Optic Neuritis

Retinal Flatmount

Microscopy

Treatment Period 5mg/kg i.p.)

Optic Neuritis

A

D

CBA

D

CB

Vehicle

Sodium ChannelBlocker

A

D

CB

Low PowerNormal

Reduced Nerve Damage

Normal mouse

Mea

n re

tina

cell

dens

ity (c

ells

/mm

2)

1000

1100

1200

1300

1400

1500

1600

1700

1800

1900

OPTIC NEURITIS+ Vehicle

OPTIC NEURITIS +drug


NEUROPROTECTION WITH SODIUM CHANNEL BLOCKERS

OPTIC NEURITIS

Gabilondo I et al. 2015

Change in Retinal Nerve Fibre Layer Thickness after Optic Neuritis

Double blind, randomised placebo-controlled, parallel group design

Initial dose 15 mg/kg, daily 4 mg/kg (max 300mg) , treatment duration 3 monthsBlinded assessing and treating physicians; 2 imaging sites (Sheffield, London)Outcomes OCT, VEP, MRI, Vision



OPTIC NEURITIS TRIAL



300 pwMS

Year 1 Year 2 Year 3

600 pwM

300 pwMS

Active tablet

Placebo tablet

Year -2

Year 4

Month6

Active tablet

Placebo tablet

-6month

month 18

Month12

LP1 LP2 LP3

STANDARD TRIAL DESIGN

NOVEL TRIAL DESIGN

30 pwMS

30 pwMS

60 pwMS



DMT + Nerve protector

DMT

UCL-INSTITUTE OF NEUROLOGYQueen SquareUCL-INSTITUTE OF NEUROLOGYQueen SquareUCL-INSTITUTE OF NEUROLOGYQueen Square THANK YOU FOR LISTENING

Spasticity StudiesDavid Baker Gareth Pryce Gavin Giovannoni

Neuroprotection StudiesDavid Baker Gareth Pryce Sarah Al-IzkiKatie LidsterSam JacksonGavin Giovannoni

Optic Neuritis TrialRaj Kapoor, Rhian Raftopoulos, Simon Hickman, Basil SharrockKlaus Schmierer, Gavin GiovannoniDavid H Miller & Others

Slides Available on www.ms-res.org(Slideshare)

http://www.ms-res.org/

Date post:	23-Jan-2018
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