Download - The charcot project - antivirals to treat MS
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The Charcot Project: Antiviral Therapies for MS
Gavin Giovannoni
Version 2.0
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Disclosures
Over the last 15 years I have received personal compensation for
participating in advisory boards in relation to clinical trial design, trial steering
committees, and data and safety monitoring committees from: Abbvie,
Almirall, Atara Bio, Bayer-Schering Healthcare, Biogen, Canbex, Eisai, Elan,
Fiveprime, Genzyme, Genentech, GSK, GW Pharma, Ironwood, MSD, Merck
Serono, Novartis, Pfizer, Roche, Sanofi, Synthon BV, Teva, UCB Pharma and
Vertex Pharmaceuticals
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The case for MS being due to a virus
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To cure MS do we need to know the cause?
EBV, HERVs, etc.
Vitamin D, Obesity (? diet)
Smoking, organic solvents
Genes(HLA,....)
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The MS 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
pathobiology
clinical outcomes
biomarkersPremature Ageing
Genetics Environment Chance
VIRUS(EBV, HERVs)
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.
Epidemics or clusters of MS
• No documented cases of MS
on the Faroe Islands until
after World War II
• 55 cases since 1940
• Occupied during World War
II
• Authors concluded that this
was evidence of an MS
epidemic caused by an agent
introduced by the troops
• However a number of
concerns remain
The annual incidence of MS (per 100 000
inhabitants) in the Faroe Islands since 1940
Kurtze et al 1993
0
2
4
6
8
10
12
1940 1945 1950 1955 1960 1965 1970 1975 1980 1985 1990
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Relapsing and Remitting Multiple Sclerosis: Pathology of the Newly Forming Lesion
Barnett & Prineas. Ann Neurol 2004;55:458–468
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Magnetization Transfer Changes in the Normal Appearing White Matter Precede the Appearance of Enhancing Lesions in Patients with Multiple Sclerosis
Filippi et al. Ann Neurol 1998;43:809-814
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Bermel et al. Ann Neuol 2012.
Predictors of long-term outcome in MSers treated with interferon beta-1a
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REBOUND ACTIVITY AFTER NATALIZUMAB/FINGOLIMOD WITHDRAWAL
Rigau et al. Neurology 2012;79:2214-6.Alroughani et al. BMJ Case Rep. 2014 Oct 15;2014. pii: bcr2014206314.
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REBOUND AFTER NATALIZUMAB WITHDRAWAL
Rigau et al. Neurology 2012;79:2214-6.
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Serafini et al. J Neuroimmunol. 2017 Jun 15;307:14-17.
Massive intracerebral Epstein-Barr virus reactivation in lethal
multiple sclerosis relapse after natalizumab withdrawal.
● Highly-active RRMS, severe
neurologic impairment (EDSS 7)
● Treated with natalizumab - EDSS 4.5
● Due to severe depression, stopped
Nz after 37 infusions.
● 3½ months later rapid disease
worsening
● Brain MRI showed >50 T2-lesions,
mostly Gd-enhancing
● JCV-PCR -ve in CSF
● Rapidly worsened, died d17
● PM active MS rebound
● JCV-PCR -ve in brain
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Which virus?
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Infectious agents in MS
. Ramagopalan et al 2009
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MS IM
Ramagopalan et al, 2011
Pearson r = 0.70, p=0.000025
Infectious Mononucleosis and MS
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Infectious mononucleosis
Handel et al. 2010.
Small OR19,390 MS patients and 16,007 controls, p < 10-54
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EBV Seropositivity titres
99.2% vs 90.2%
. Ascherio et al, 2000
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Odds ratio of MS in subjects seronegative for EBV
Ascherio et al, 2007
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Primary infection with the EBV and risk of MS
• Nested case-control study including from over 8 million military personnel with serum stored in the Department of Defense Serum Repository.
Levin et al. Ann Neurol 2010.
MS
Controls N = 610
N = 30510/305 (3.3%) EBV –ve
32/610 (5.2%) EBV –ve 10/28 (35.7%) EBV –ve
10/10 (100%) EBV –ve
• MS risk is extremely low among individuals not infected with EBV, but it
increases sharply in the same individuals following EBV infection.
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.Levin et al. Ann Neurol 2010.
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“Evidence” or “lack of evidence”
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The ugly fact
“The great tragedy of Science; the slaying of a beautiful hypothesis by an ugly fact.”
Thomas Henry Huxley
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Viral serologies in children with MS
Banwell et al. Lancet Neurology, Sept. 2007
?
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Coherence with prior knowledge
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Compston & Coles, Lancet 2008.
Epidemiology
worldwide distribution & migration studies
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Genetics of MS: the rate of MS in females is increasing
1Orton SM et al. Lancet Neurol 2006;5:932–936.
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Smoking is a risk factor for MS
Handel et al. PLoS One. 2011 Jan 13;6(1):e16149.
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Ramagopalan et al. Arch Neurol 2011; 68:469-72.
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Biological plausibility
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EBV & Disease Activity
Farrell et al. Neurology 2009
EBNA-1
NOT
VCA or EA
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Dysregulated EBV infection in the MS brain
Serafini et al. J Exp Med. 2007 Nov 26;204(12):2899-912.
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Follow-up studies
1. Torkildsen O, et al. Upregulation of Immunoglobulin-related Genes in Cortical Sections
from Multiple Sclerosis Patients. Brain Pathol. 2009 Oct 16. [Epub ahead of print]
2. Willis SN, et al. Epstein-Barr virus infection is not a characteristic feature of multiple
sclerosis brain. Brain. 2009 Dec;132(Pt 12):3318-28.
3. Peferoen LA, et al. Epstein Barr virus is not a characteristic feature in the central nervous
system in established multiple sclerosis. Brain. 2010 May;133(Pt 5):e137. Epub 2009 Nov
16.
4. Lassmann et al. Brain. 2011 Sep;134(Pt 9):2772-86. Tzartos et al. Neurology. 2012 Jan
3;78(1):15-23.
5. Tzartos et al. Neurology. 2012 Jan 3;78(1):15-23.
6. Serafini et al. J Neuropathol Exp Neurol. 2014 Jul;73(7):729-31.
7. Serafini et al. Brain. 2013 Jul;136 (Pt7):e233. doi: 10.1093/brain/aws315.
8. Han et al. Molecular signature of Epstein-Barr virus infection in multiple sclerosis brain
lesions. ECTRIMS Online Library. Oct 27, 2017; 200600.
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Innate immune activation is a hallmark of the active MS lesions
Tzartos et al., Neurology 2012.
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Innate immune activation is a hallmark of the active MS lesions
Tzartos et al., Neurology 2012.
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Intrathecal oligoclonal IgG bands (OCBs)
1. Rand KH, et al. (1998) Molecular approach to find target(s)
for oligoclonal bands in multiple sclerosis. J Neurol
Neurosurg Psychiatry 65:48-55.
2. Bray PF, et al. (1992) Antibodies against Epstein-Barr
nuclear antigen (EBNA) in multiple sclerosis CSF, and two
pentapeptide sequence identities between EBNA and
myelin basic protein. Neurology 42:1798-804.
3. Cepok S, et al. (2005) Identification of Epstein-Barr virus
proteins as putative targets of the immune response in
multiple sclerosis. J Clin Invest 115:1352-60.
4. Rand KH, et al. (2000) Epstein-Barr virus nuclear antigen-1
(EBNA-1) associated oligoclonal bands in patients with
multiple sclerosis. J Neurol Sci 173:32-9. C+ / S-
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Analogy
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Axthelm et al. Ann Neurol 2010
Japanese Macaque Encephalomyelitis:
A Spontaneous Multiple Sclerosis–like Disease in a Nonhuman Primate
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HTLV-1 myelopathy
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Experimental evidence
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N Engl J Med 2008;358:676-88.
Please note rituximab is the only licensed anti-EBV drug!
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Baker et al. EBioMedicine. 2017 Feb;16:41-50.
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Saha & Robertson. DOI: 10.1158/1078-0432.CCR-10-2578 Published May 2011
EBV & B-cell
biology
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Sir Bradford-Hill: Criteria for Causation
Bradford-Hill A. The environment and disease: association or causation? Proc Royal Soc Med 1966; 58:295.
1. CONSISTENCY AND UNBIASEDNESS OF FINDINGS - Yes (not 100%)
2. STRENGTH OF ASSOCIATION – ? / Yes (RR ~ 2 to 3)
3. TEMPORAL SEQUENCE - Yes
4. BIOLOGICAL GRADIENT (DOSE-RESPONSE RELATIONSHIP) - ? (not relevant to infections)
5. SPECIFICITY – No (not 100% other putative autoimmune diseases also associated with
EBV)
6. COHERENCE WITH BIOLOGICAL BACKGROUND AND PREVIOUS KNOWLEDGE - No
7. BIOLOGICAL PLAUSABILITY - Yes
8. REASONING BY ANALOGY - Yes
9. EXPERIMENTAL EVIDENCE - No
EBV is the cause of MS, but we don’t know how it causes MS!
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Dual-viral hypothesis
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Charcot Project: viral aetiology
HIV and lower risk of MS: beginning to unravel a mystery using a record-linked database study
Nexø et al. Epidemiology 2013; 24:331-2
Treatment of HIV and Risk of Multiple Sclerosis
Gold et al. JNNP August 4, 2014 as 10.1136/jnnp-2014-307932.
Raltegravir → RRMS (INSPIRE STUDY)ClinicalTrials.gov ID: NCT01767701
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Endogenous retroelements and autoimmune disease
Volkman & Stetson. Nat Immunol 2014
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HERV-W-Env Protein Pathogenicity
HERV-W-Env protein
The envelope protein of HERV-W
Typically not expressed in healthy individuals.
Abnormal expression triggered by environmental factors (EBV…)
Appears to be involved in Multiple Sclerosis pathogenesis.
Activation of TLR4 pathway
by HERV-W-Env
Immune system
➢ Inflammation
➢ Autoimmunity
Non-immune cells
➢ Endothelial cells: inflammatory
responses
➢ Schwann cells: inflammatory
responses
➢ Oligodendrocytes precursor cells:
differentiation / remyelination blockade
GNbAC1A monoclonal humanized antibody
neutralizing HERV-W-Env
Successful Phase I and Phase IIa clinical trials in MS indication
Currently in Phase IIb efficacy clinical trial
HERV-W-Env
HERV-W-Env – TLR4 signaling pathway
Perron H et al. Virology. 2001;
Rolland A et al. J Immunol. 2006;
Kremer D, et al. Ann Neurol. 2013
Duperray A et al. Int Immunol. 2015;
Madeira et al. 2016, J Neuro Immunol;
Faucard et al. 2015, Ebiomedic;
Curtin et al. 2016, MS Relat DisordSlide courtesy : Hervé Perron
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▪ Phase I Study completed in January 2012/validated July 2012
Excellent safety profile; No immunogenicity; PK is dose linear; Half-life compatible with
monthly administration
GNbAC1 a Humanized IgG4 antibody
neutralizing HER-W Env in Clinical trials
Curtin et al. Clin. Ther. 2012
▪ Phase IIa 1 year Study in MS patients with monthly infusions completed in March 2014:
promising data for GNbAC1.
▪ Excellent safety profile; No immunogenicity; MRI stability and no progression, notably
in PMS
▪ Safe mode of action validated in patients: No modification of any physiological
immune function in one-year treated patients (Normal profile of immune cell sub-
popuplations and responses to Immunity test panel in all patients…)
▪ Beyond expected simple effects of an “toxin-neutralizing” antibody.
Curtin et al. Mult. Scler. 2014
▪ Phase IIb efficacy Study Started in 2016: 10 European countries; 320 patients;
ascending doses (6, 12, 18 mg/Kg) and placebo; 1 year Monthly injections;
patients.
▪ Final 1-year results expected in March 2018.
Slide courtesy : Hervé Perron
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HERV-W genomic structure as sequenced from MSRV virions
May antiretroviral drugs inhibit the expression of HERV-
W genome when activated ?
Slide courtesy : Hervé Perron
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HERV-W endogenous retroviruses and MS
Dolei, MSJ 2018, Vol. 24(1) 42–47.
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Targeting HERVs
BioEssaysVolume 35, Issue 9, pages 794-803, 17 JUL 2013 DOI: 10.1002/bies.201300049http://onlinelibrary.wiley.com/doi/10.1002/bies.201300049/full#bies201300049-fig-0001
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INSPIRE: Raltegravir (Isentress) Pilot Study in Relapsing MS
change in gradient
change
(in means)
V1
V2
(screening
before
visit)V3 V4 V5 V6 V7
V8 after
Raltegravir
dispensed
A statistically significant
change in means is not in
this situation consistentwith a reduction inoutcome values due to
intervention.Raltegravir → RRMS (INSPIRE STUDY)ClinicalTrials.gov ID: NCT01767701
Slide courtesy : Julian Gold
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PREVENTION
DISEASE
MODIFICATION
1. Epidemiologists
2. Virologists
3. Genomics
4. Bioinformatics
5. Immunologists
6. Neurologists
7. Pharmaceuticals
EBV
? mutations
Conclusion: ‘The Charcot Project’- EBV & HERVs
Early infection
Late infection
Asymptomatic
seroconversion
Infectious
mononucleosis
At risk MS
vD/Sunlight Obesity
Genetics
Vaccine
IM Rx
Anti-EBV
HAART
HERVs
GNbAC1
Smoking
Diet
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Arthur Schopenhauer
(1788 –1860)
All truth passes through three stages:
• It is ridiculed
• It is violently opposed
• It is accepted as self-evident
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Is there a “Black Swan” flying in?
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AcknowledgementsQMUL:
Ute Meier
Monica Marta
Sreeram Ramagopalan
Ruth Dobson
Jo Topping
Georgina Burrow
Cosimo Maggiore
Hadi Amir-Maghzi
Chris Hawkes
Klaus Schmierer
David Baker
Jack Cuzick
Nick Wald
David Holden
Oxford:
George Ebers
Sreeram Ramagopalan
Adam Handel
Giulio DeSanto
Epidemiology, Oxford:
Raph Goldacre
Michael Goldacre
David Yeates
The Albion Centre, Sydney:
Julian Gold
Hubert Maruszak
UCL:
Robin Weiss
Rachel Farrell
Jeremy Garson
VU Amsterdam:
Jaap Middeldorp
Sandra Amor
Edinburgh:
Dorothy Crawford
Karen McCauley
Aarhus University:
Tove
Christiansen