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My presentation at the MS Trust 2012 meeting in Kenilworth! What a rainy and rushed day. May be next time I will be more relaxed.
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Immunology and the roots of MS
MS Trust Annual Conference 2012 For health and social care professionals
Gavin Giovannoni
Barts and The London School of Medicine and Dentistry
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Current Dogma
immune activation innate and adaptive responses
focal inflammation
BBB breakdown
oligodendrocyte toxicity & demyelination
Acute axonal transection and loss
“autoimmune endophenotype”
axonal plasticity & remyelination
delayed neuroaxonal loss and gliosis - biology
Current Dogma
immune activation innate and adaptive responses
focal inflammation
BBB breakdown
oligodendrocyte toxicity & demyelination
Acute axonal transection and loss
“autoimmune endophenotype”
axonal plasticity & remyelination
delayed neuroaxonal loss and gliosis - biology
Clinical Attack
Disease Progression
Clinical Recovery
- clinical outcomes
Current Dogma
immune activation innate and adaptive responses
focal inflammation
BBB breakdown
oligodendrocyte toxicity & demyelination
Acute axonal transection and loss
“autoimmune endophenotype”
axonal plasticity & remyelination
delayed neuroaxonal loss and gliosis - biology
Clinical Attack
Disease Progression
Clinical Recovery
- clinical outcomes
Gd-enhancement
T2 & T1 lesions
brain & spinal cord atrophy
release of soluble markers
- biomarkers
Current Dogma
immune activation innate and adaptive responses
focal inflammation
BBB breakdown
oligodendrocyte toxicity & demyelination
Acute axonal transection and loss
“autoimmune endophenotype”
axonal plasticity & remyelination
delayed neuroaxonal loss and gliosis
Gd-enhancement
T2 & T1 lesions
brain & spinal cord atrophy
release of soluble markers
Clinical Attack
Disease Progression
Clinical Recovery
- biology
- clinical outcomes
- biomarkers
Current Dogma
immune activation innate and adaptive responses
focal inflammation
BBB breakdown
oligodendrocyte toxicity & demyelination
Acute axonal transection and loss
“autoimmune endophenotype”
axonal plasticity & remyelination
delayed neuroaxonal loss and gliosis
Gd-enhancement
T2 & T1 lesions
brain & spinal cord atrophy
release of soluble markers
Clinical Attack
Disease Progression
Clinical Recovery
- biology
- clinical outcomes
- biomarkers
.
Interferon-beta Glatiramer acetate
Mitoxantrone Natalizumab
Fingolimod Teriflunomide Alemtuzumab
BG12 Cladribine
Rituximab/Ocrelizumab Daclizumab
Martino et al. Lancet Neurology 2002; 1:499-509.
RRMS: pathology of the newly forming lesion
Barnett & Prineas. Ann Neurol 2004;55:458–468.
Coles et al. J Neurol. 2006 Jan;253(1):98-108..
Post-inflammatory neurodegeneration
.
Neuroprotection
Rationale for sodium channel blockade
Waxman SG. Nat Rev Neurosci. 2006 Dec;7(12):932-41. Videos courtesy Hugh Bostock, Inst. Neurol., UCL
Bechtold et al. Ann Neurol 2004;55:607–616
Secondary progressive EAE
Pryce et al. Brain 2003;126:2191-202.
Time (Days)
10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85
Mea
n C
linic
al S
core
± S
EM
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
4.5
Vehicle Cannabinoids
TREATMENT
Neuroprotection
Aims of CUPID study
• to assess the value of Δ9-THC in slowing progressive MS over 3 years.
• to assess the safety of Δ9-THC over the long-term. • to improve research methodology by using new,
patient-orientated methods.
Slide courtesy of Prof. John Zajicek
0 200 400 600 800 1000 1200
0.0
0.2
0.4
0.6
0.8
1.0
Time to EDSS progression (days)
P(E
DS
S p
rog
ressio
n)
Treatment group
Active
Placebo
Slide courtesy of Prof. John Zajicek
Year 3 Year 4 Year 5
560 MS’ers
280 MS’ers with PPMS or SPMS
Year 1 Year 2 Year 6 Year 7
Recruitment Trial Data analysis Registration
Not 7 years, but 10 years
Cannabinoid Use in Progressive Inflammatory brain Disease (CUPID)
280 MS’ers with PPMS or SPMS
Waxman SG. Nat Rev Neurosci. 2006 Dec;7(12):932-41.
Neuroprotective targets
Petzold et al. J Neurol Neurosurg Psychiatry. 2005 Feb;76(2):206-11.
Spinal fluid neurofilament levels
Recruitment Trial Data analysis
6 months
6 months 60 MS’ers
6 months
LP2 LP3 LP4
30 MS’ers active tablet
30 MS’ers placebo tablet
2 years
6 months
LP1
38 year old woman with left optic neuritis
sTE fFLAIR images
Baseline 52 weeks
Hickman et al. Neuroradiology 2001;43:123-8.
Trapp et al. N Engl J Med 1998.
Acute mono-focal lesion
CFM6104 Induces Neuroprotection in Optic Neuritis (Nerve Content)
Reduced Nerve Damage
Normal mouse
Mea
n r
etin
a ce
ll d
ensi
ty (
cells
/mm
2)
1000
1100
1200
1300
1400
1500
1600
1700
1800
1900
OPTIC NEURITIS
+ Vehicle OPTIC NEURITIS +
CFM6104
P<0.01
NEUROPROTECTIVE STRATEGIES IMMUNE-DEPENDENT
NEURODEGENERATION
Acute neuroprotection
Ischemic penumbra
Ischemic penumbra
Neu
rop
rote
ctio
n
Time Post-Disease Induction (days).
32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
Vehicle
CFMA D33-D48 Hindlimb
Paralysis
Hindlimb
Paresis
Impaired
Right
Reflex
Tail Paresis
Tail
Paralysis
Period of Daily Treatment
No Immunosuppression Evident
ROTAROD ACTIVITY
Measure of Motor Co-ordination
Pre-Treatment (Day 27)
0
50
100
150
200
250
300
Post- Relapse (Day 48)
***
Neu
ropr
otec
tion
Mea
n N
euro
logi
cal
Sco
re ±
SEM
Tim
e of
on
Acc
eler
atin
g R
otaR
od (
s)
CFMA Induces Neuroprotection in EAE
Immunologic penumbra
Is the current dogma wrong?
immune activation innate and adaptive responses
focal inflammation
BBB breakdown
oligodendrocyte toxicity & demyelination
Acute axonal transection and loss
“autoimmune endophenotype”
axonal plasticity & remyelination
delayed neuroaxonal loss and gliosis
Gd-enhancement
T2 & T1 lesions
brain & spinal cord atrophy
release of soluble markers
Clinical Attack
Disease Progression
Clinical Recovery
- biology
- clinical outcomes
- biomarkers
Is the current dogma wrong?
immune activation innate and adaptive responses
focal inflammation
BBB breakdown
oligodendrocyte toxicity & demyelination
Acute axonal transection and loss
“autoimmune endophenotype”
axonal plasticity & remyelination
delayed neuroaxonal loss and gliosis
Gd-enhancement
T2 & T1 lesions
brain & spinal cord atrophy
release of soluble markers
Clinical Attack
Disease Progression
Clinical Recovery
- biology
- clinical outcomes
- biomarkers
Is the current dogma wrong?
immune activation innate and adaptive responses
focal inflammation
BBB breakdown
oligodendrocyte toxicity & demyelination
Acute axonal transection and loss
“autoimmune endophenotype”
axonal plasticity & remyelination
delayed neuroaxonal loss and gliosis
Gd-enhancement
T2 & T1 lesions
brain & spinal cord atrophy
release of soluble markers
Clinical Attack
Disease Progression
Clinical Recovery
- biology
- clinical outcomes
- biomarkers
Virus?
Genes
Environment Chance
MS is a complex disease
Ramagopalan, Dobson, Meier, Giovannoni. Lancet Neurol. 2010 Jul;9(7):727-39.
MS Endophenotype
Conclusions • MS is complex disease
– The immune system is clearly involved (primary or secondary)
– MS endophenotype (imprinting beginning in utero) suggests MS may be a preventable disease
• Has the emergence of monoclonal therapies cracked the relapsing or inflammatory phase of the disease?
• Progressive MS remains a problem
– The challenge is doing affordable phase 2 & 3 trials
– We need new outcome measures and clinical trials
• Is the immunological dogma wrong?
– Is MS ready for a paradigm shift; for example anti-viral therapies?
– The Charcot Project
• www.ms-res.org
www.ms-res.org