5th uclp ms research day curing ms

Why haven’t we cured MS yet?

Gavin Giovannoni

Barts and The London

To cure MS do we need to know the cause?

EBV Vitamin D

Smoking Genes

We work on the hypothesis that MS is an autoimmune disease.

Multiple

Sclerosis

Environ-ment

Genes

The autoimmune hypothesis

Multiple

Sclerosis

Environ-ment

Genes

What does a cure mean?

Dis

abili

ty

Time

delayed worsening 1 stabilised 2

improved function 3 recovered function 4

What does a cure mean?

MRI Lesions

1st clinical attack

Time (Years)

Asymptomatic disease

Inflammation

Brain volume loss

Nerve cell loss

Dis

eas

e S

eve

rity

SPMS RRMS

1st MRI lesion

Relapses

CIS RIS R-SPMS

RIS = radiologically isolated syndrome (asymptomatic MS) CIS = clinically isolated syndrome RRMS = relapsing-remitting MS R-SPMS = relapsing secondary progressive MS SPMS = secondary progressive MS PPMS = primary progressive MS

PPMS

The therapeutic window for recovery

MRI Lesions

1st clinical attack

Time (Years)

Asymptomatic disease

Inflammation

Brain volume loss

Nerve cell loss

Dis

eas

e S

eve

rity

SPMS RRMS

1st MRI lesion

Relapses

CIS RIS R-SPMS

RIS = radiologically isolated syndrome (asymptomatic MS) CIS = clinically isolated syndrome RRMS = relapsing-remitting MS R-SPMS = relapsing secondary progressive MS SPMS = secondary progressive MS PPMS = primary progressive MS

PPMS

EDSS < 4.0 / ? Age < 40

The therapeutic window for recovery

Survival Curves

85%

50%

30%

0%

15yrs 25yrs 40yrs 50yrs

100% Benign MS

Proportioned of treated MSers are cured

Natural history

Unrealistic expectation

Delayed onset of SPMS

Defining a cure: a working definition

85%

50%

30%

0%

15yrs 25yrs 40yrs 50yrs

100%

Proportioned of treated MSers are cured

Natural history

NEDA = no evident disease activity

The autoimmune hypothesis

Multiple

Sclerosis

Environ-ment

Genes

Day 7

Limp tail

Impaired righting reflex

hindlimb paralysis

Moribund

partial paralysis

Normal

Remission

0

1

2

3

4

5

(1)

Clinical Score Professor Baker’s

Animal model of MS

Day 0

Slide courtesy David Baker

Curing animal MS

survival analysis

“highly effective treatments”

MS is an autoimmune disease hypothesis

15-20 year experiment

Can we repeat the animal experiment in MS?

Multiple

Sclerosis

Environ-ment

Genes

Relapses

Unreported relapses

Clinical disease worsening

Subclinical relapses: focal MRI activity

Focal gray and white matter lesions not detected by MRI

Brain atrophy

Spinal fluid neurofilament levels

Moving the target: the MS Iceberg

Clinical activity

Focal MRI activity

Hidden focal and diffuse MRI activity

Microscopic or biochemical pathology

Biomarkers

Control Multiple sclerosis

Moving the target: end-organ damage

NEDA

Gd, gadolinium. 1. Havrdova E, et al. Lancet Neurol 2009; 8:254–260; 2. Giovannoni G, et al. Lancet Neurol 2011; 10:329–337.

Treat-2-target

Brain volume loss should be included in our definition for NEDA

No evidence of disease activity defined as:1,2

× No relapses

× No sustained worsening of disability

× No MRI activity

× No new or enlarging T2 lesions

× No Gd-enhancing lesions

Have we got it wrong?

EBV Vitamin D

Smoking Genes

Multiple

Sclerosis

Environ-ment

Genes

Is MS due to a virus?

Charcot Project

INSPIRE Trial (Raltegravir)

Etc. etc. etc.

Why haven’t we cured MS yet?

We may have, we need time to tell, or alternatively a black swan may fly in to the change the time-line.