Role of biomarkers in blood and CSF
Gavin Giovannoni
Barts and The London
Why MS biomarkers?
• Diagnostic testing
• Positive & negative predictive testing
• Pathogenesis
• Immunology
• Aetiology
•...
Diagnostic & pathogenic markers
The evolving clinical definition of MS
1. Schumacher, et al. Problems of Experimental Trials of Therapy in Multiple Sclero...
Will Rogers Phenomenon in Multiple Sclerosis
1879 - 1935
“When the Okies left Oklahoma and moved to California,
they raise...
Will Rogers Phenomenon in Multiple Sclerosis
Sormani et al. Ann Neurol 2008;64:428–433.
Poser
McDonald
Intrathecal synthesis of IgG
Images courtesy of Alastair Compston and Ed Thompson.
Kabat et al. J Clin Invest. 1942 Sep;21...
Diagnostic criteria for Primary Progressive MS
Polman et al. Ann Neurol 2005;58:840-6.
Accumulation of disability in PPMS:
stratified by intrathecal IgG abnormalities
Proportion Progressing as Percent
Epoch CS...
Dobson R, et al. J Neurol Neurosurg Psychiatry 2013;0:1–6.
What constitutes a useful diagnostic test or set of criteria?
TARGET DISORDER
PRESENT ABSENT
DIAGNOSTIC
TEST RESULT
+ a b ...
A clinico-pathoanatomical study of multiple sclerosis diagnosis
SENSITIVITY = True+ve /(True+ve + False-ve)
Eye Department...
Lennon et al. Lancet 2004;364:2106-12.
NMO
Kleinschmidt-DeMasters,et al. N Engl J Med. 2005 Jul 28;353(4):369-74.
PML complicating treatment with natalizumab and IFN...
Pathogenic markers
“Inflammation”
“Oligodendrocyte
Toxicity &
Demyelination”
Axonal Toxicity
(conduction block)
Axonal &
Neuronal Loss
Gliosi...
Meningeal B-cell follicles in secondary progressive multiple sclerosis
associate with early onset of disease and severe co...
Increased urinary free immunoglobulin
light chain excretion in MS
Brain atrophy
Slider courtesy of Dr Nic Losseff, Institute of Numerology, Queen Square.
Control Multiple sclerosis
Brain atrophy
Petzold et al. J Neurol Neurosurg Psychiatry. 2005 Feb;76(2):206-11.
Spinal fluid neurofilament levels
Gunnarsson et al. Ann Neurol 2010; Epub.
CSF NFL
Natalizumab treatment of
progressive multiple sclerosis reduces
inflammation and tissue damage
- results of a phase 2A pro...
Natalizumab treatment of progressive MS reduces inflammation
and tissue damage: CSF markers of axonal damage
Romme Christe...
-1.0%
-0.8%
-0.6%
-0.4%
-0.2%
0.0%
Years 0-2
-0.82%
-0.80%
P=0.822
Placebo (N=315) Natalizumab (N=627)
Year 0-1* Year 1-2
...
B
aseline
Follow
-up
0
500
1000
1500
2000
2500
NfL(pg/ml)
Baseline
Follow
-up
0
1000
2000
10000
NfL(pg/ml)
Cerebrospinal f...
Fingolimod has an early and sustained effect on the rate
of brain atrophy compared with placebo and IFNb-1a IM
FREEDOMS, 2...
Very low risk
age
place of residence
outdoor activity / sun exposure / sun screen
diet / vitamin D supplements
age of expo...
d25-OH D3
Cox univariate HR 95% CI P value
Q1 1.00
Q2 0.74 0.60-0.92 0.008
Q3 0.69 0.55-0.90 0.001
Q4 0.74 0.60-0.92 0.007...
EBNA-1 IgG*
Cox univariate HR 95% CI P value
EBNA-1 nOD 1.01 0.996-1.029 0.137
* similar results in OCB pos and MRI T2 pos...
Pharmacovigilance markers
What is the diagnosis?
Take special care with Interferon-beta-1b:
If you might have a disorder of the immune system in which
abnormal proteins ar...
?
Natalizumab
Progressive multifocal leukoencephalopathy (PML)
Kleinschmidt-DeMasters,et al. N Engl J Med. 2005 Jul 28;353(4...
Natalizumab PML risk stratification tool
Anti-JC virus antibody status
Negative Positive
Prior immunosuppressant use
Natal...
PML risk estimates for anti-JCV antibody index thresholds were calculated based on the current PML risk stratification alg...
Predicting autoimmunity following treatment of MS with alemtuzumab
• 30% of alemtuzumab-treated pts
develop autoimmune sid...
Neurology 2012;78(Suppl.): [S41.006]
Anti-natalizumab Antibodies
Number of Patients at Risk
Placebo
Antibody Negative
Transiently Positive
Persistently Positiv...
Natalizumab infusion reactions
• Acute hypersensitivity reactions are well-recognized
• Generalized urticaria, dizziness, ...
Monitoring effect of therapeutic interventions
Reduced efficacy due to NAbs – systematic review
Farrell & Giovannoni, Multiple Sclerosis 2007; 13: 567-577.
Clinical importance of neutralising antibodies against interferon
beta in patients with relapsing-remitting multiple scler...
Jacob Elkins, James Sheridan, Lakshmi Amaravadi,
Katherine Riester, Gilmore O’Neill
Neurology 2012;78(Suppl.): S31.004
Prognostic markers
Intrathecal synthesis of IgG
Images courtesy of Alastair Compston and Ed Thompson.
Kabat et al. J Clin Invest. 1942 Sep;21...
Petzold, J Neurol Sci. 2005 Jun 15;233(1-2):183-98.
Conclusion
• Diagnostic/prognostic biomarkers
• Intrathecal OCBs
• IgG Index
• Pharmacovigilance
• Baseline screening
• Mo...
Acknowledgements
• Giovannoni
• Sharmilee Gnanapavan
• David Baker
• Gareth Pryce
• Sarah Al-Izki
• Sam Jackson
• Katie Li...
Biomarkers in MS
Biomarkers in MS
Biomarkers in MS
Biomarkers in MS
Biomarkers in MS
Biomarkers in MS
Biomarkers in MS
Biomarkers in MS
Biomarkers in MS
Biomarkers in MS
Biomarkers in MS
Biomarkers in MS
Biomarkers in MS
Biomarkers in MS
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Biomarkers in MS

  1. 1. Role of biomarkers in blood and CSF Gavin Giovannoni Barts and The London
  2. 2. Why MS biomarkers? • Diagnostic testing • Positive & negative predictive testing • Pathogenesis • Immunology • Aetiology • Disease progression & recovery • Disease heterogeneity • Pharmacovigilance • Monitor disease processes • Prognosis (high vs. low risk patients) • Monitoring effect of therapeutic interventions
  3. 3. Diagnostic & pathogenic markers
  4. 4. The evolving clinical definition of MS 1. Schumacher, et al. Problems of Experimental Trials of Therapy in Multiple Sclerosis: Report by the Panel on the Evaluation of Experimental Trials of Therapy in Multiple Sclerosis. Ann N Y Acad Sci 1965;122:552-68. 2. Poser, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983;13:227-31. 3. McDonald, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 2001;50:121-7. 4. Polman, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the "McDonald Criteria". Ann Neurol 2005;58:840-6. 5. Polman, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 2011;69:292-302.
  5. 5. Will Rogers Phenomenon in Multiple Sclerosis 1879 - 1935 “When the Okies left Oklahoma and moved to California, they raised the average intelligence level in both states.”
  6. 6. Will Rogers Phenomenon in Multiple Sclerosis Sormani et al. Ann Neurol 2008;64:428–433. Poser McDonald
  7. 7. Intrathecal synthesis of IgG Images courtesy of Alastair Compston and Ed Thompson. Kabat et al. J Clin Invest. 1942 Sep;21(5):571-7. Carl Lange – Colloidal Gold Curve Isoelectric focusing with immunfixation
  8. 8. Diagnostic criteria for Primary Progressive MS Polman et al. Ann Neurol 2005;58:840-6.
  9. 9. Accumulation of disability in PPMS: stratified by intrathecal IgG abnormalities Proportion Progressing as Percent Epoch CSF- CSF+ 6 mo 7.3 9.8 12 mo 15.0 20.4 18 mo 22.8 28.1 24 mo 25.4 34.3 Years to Progression 2.43 2.26 Based on data from a second meeting of the DSMB and assume no therapeutic effect 0 1 2 3 Years 0.0 0.2 0.4 0.6 0.8 1.0 ProportionProgressing Positive Negative CSF Slide courtesy of Jerry Wolinsky P =0.03
  10. 10. Dobson R, et al. J Neurol Neurosurg Psychiatry 2013;0:1–6.
  11. 11. What constitutes a useful diagnostic test or set of criteria? TARGET DISORDER PRESENT ABSENT DIAGNOSTIC TEST RESULT + a b a + b - c d c + d a + c b + d a + b + c + d From these we determine the sensitivity and specificity as follows: SENSITIVITY = a/(a+c) > 80% SPECIFICITY = d/(b+d) > 80% Neurobiol Aging 1998; 19:109-116.
  12. 12. A clinico-pathoanatomical study of multiple sclerosis diagnosis SENSITIVITY = True+ve /(True+ve + False-ve) Eye Department, Hvidovre Hospital, Denmark. • Neuropathological examination of 518 consecutive patients with clinically definite MS revealed a correct diagnosis in 485 cases (94%). • Clinical diagnosis had been established by a neurologist in all cases. • Erroneous diagnosis included a variety of other neurological disorders. • Also investigated was a randomly selected series of 33 patients with a clinical diagnosis of probable MS: – post mortem confirmation of MS was obtained in circa 66%. – The remainder the error pattern was similar to the above. Engell T. Acta Neurol Scand. 1988 Jul;78(1):39-44.
  13. 13. Lennon et al. Lancet 2004;364:2106-12. NMO
  14. 14. Kleinschmidt-DeMasters,et al. N Engl J Med. 2005 Jul 28;353(4):369-74. PML complicating treatment with natalizumab and IFNb-1a for MS
  15. 15. Pathogenic markers
  16. 16. “Inflammation” “Oligodendrocyte Toxicity & Demyelination” Axonal Toxicity (conduction block) Axonal & Neuronal Loss Gliosis Remyelination & Axonal Recovery “Inflammation” Central Adaptation & Plasticity Key pathological processes in MS
  17. 17. Meningeal B-cell follicles in secondary progressive multiple sclerosis associate with early onset of disease and severe cortical pathology Magliozzi et al. Brain 2007; 130:1089-1104.
  18. 18. Increased urinary free immunoglobulin light chain excretion in MS
  19. 19. Brain atrophy Slider courtesy of Dr Nic Losseff, Institute of Numerology, Queen Square.
  20. 20. Control Multiple sclerosis Brain atrophy
  21. 21. Petzold et al. J Neurol Neurosurg Psychiatry. 2005 Feb;76(2):206-11. Spinal fluid neurofilament levels
  22. 22. Gunnarsson et al. Ann Neurol 2010; Epub. CSF NFL
  23. 23. Natalizumab treatment of progressive multiple sclerosis reduces inflammation and tissue damage - results of a phase 2A proof-of-concept study ClinicalTrials.gov Identifier: NCT01077466 J. Romme Christensen1, R. Ratzer1, L. Börnsen1, E. Garde2, M. Lyksborg2, H.R. Siebner2, T.B. Dyrby2, P. Soelberg Sørensen1 and F. Sellebjerg1
  24. 24. Natalizumab treatment of progressive MS reduces inflammation and tissue damage: CSF markers of axonal damage Romme Christensen et al. ECTRIMS 2012.
  25. 25. -1.0% -0.8% -0.6% -0.4% -0.2% 0.0% Years 0-2 -0.82% -0.80% P=0.822 Placebo (N=315) Natalizumab (N=627) Year 0-1* Year 1-2 -0.40% -0.56% -0.43% -0.24% P=0.004 P=0.002 Miller DH et al. Neurology 2007;68:1390-1401. Natalizumab and brain atrophy Mean (SE) percentage change in BPF
  26. 26. B aseline Follow -up 0 500 1000 1500 2000 2500 NfL(pg/ml) Baseline Follow -up 0 1000 2000 10000 NfL(pg/ml) Cerebrospinal fluid NfL Fingolimod 0.5mg/1.25 mg versus placebo treated patients p<0.001 Fingolimod, n=23 Placebo, n=12 p=0.470 Fingolimod 0.5 mg Fingolimod 1.25 mg Baseline Follow-up Baseline Follow-up Median (pg/ml) 644 321 (-50%) 886 738 (-17%) *Non-parametric Wilcoxon matched pairs test; p value is calculated with inclusion of outliers Dr Jens Khule, ECTRIMS 2013
  27. 27. Fingolimod has an early and sustained effect on the rate of brain atrophy compared with placebo and IFNb-1a IM FREEDOMS, 2 years Fingolimod 0.5 mg (n = 356) Placebo (n = 329) *** * ** 60 12 24 Time (months) 0 -0.4 -0.8 -1.2 -1.6 -2.0 −38% vs placebo p<0.001 ChangeinmeanBVfrom baseline(%) TRANSFORMS, 1 year 0 12 Time (months) 0.0 -0.4 -0.6 -1.0 IFNb-1a IM (n = 359) Fingolimod 0.5 mg (n = 368) −40% vs IFNb-1a IM p<0.001 ***-0.2 -0.8 ChangeinmeanBVfrom baseline(%) ITT population with evaluable MRI images. Note: n numbers for FREEDOMS data reflect the number of patients with available data at 24 months. *p<0.05; **p<0.01; ***p<0.001 vs comparator; p-values are for comparisons over Months 0-6, Months 0-12, Months 0-24 BV, brain volume; ITT, intent-to-treat. Gilenya™ Prescribing Information 19 April 2012. Reproduced with permission. Kappos L et al. N Engl J Med 2010; 362: 387-401, and Cohen JA et al. N Engl J Med 2010; 362: 402-415. Copyright © 2011 Massachusetts Medical Society. All rights reserved
  28. 28. Very low risk age place of residence outdoor activity / sun exposure / sun screen diet / vitamin D supplements age of exposure to EBV smoking At risk High Risk Low risk RIS CIS MS family history genetics sex month of birth place of birth Unfavourable disease-modifying factorsdynamic risk factorsstatic risk factors dynamic protective factorsstatic protective factors MRI / evoked potentials changes Peripheral immunological changes T-regs (), NK cells, CD8 () Clinical disease In utero childhood Adolescence / early adulthood adulthood 1. Declining Physiology – “peripheral immunological endophenotype” 2. Biological disease threshold – “CNS endophenotype” 3. Asymptomatic disease – RIS (abnormal MRI and/or evoked potentials) 4. Clinical disease a. Clinically isolated syndrome (CIS) b. Relapsing MS c. Relapsing secondary progressive MS d. Non-relapsing secondary progressive MS Favourable disease-modifying factors protective HLA haplotypes CNS changes (OCBs and microscopic pathology) 2 3 24b 24c 24d 24a 1 The MS ‘Endophenotype’
  29. 29. d25-OH D3 Cox univariate HR 95% CI P value Q1 1.00 Q2 0.74 0.60-0.92 0.008 Q3 0.69 0.55-0.90 0.001 Q4 0.74 0.60-0.92 0.007 Median Survival (days) Log-rank p > Median 1267 0.021 < Median 973 Dr Jens Khule, ECTRIMS 2013
  30. 30. EBNA-1 IgG* Cox univariate HR 95% CI P value EBNA-1 nOD 1.01 0.996-1.029 0.137 * similar results in OCB pos and MRI T2 pos patients only Median Survival (days) Log-rank p < Median 1247 0.216 > Median 1032 Dr Jens Khule, ECTRIMS 2013
  31. 31. Pharmacovigilance markers
  32. 32. What is the diagnosis?
  33. 33. Take special care with Interferon-beta-1b: If you might have a disorder of the immune system in which abnormal proteins are found in the blood (monoclonal gammopathy), you must check this with your doctor before you use interferon beta-1b. Patients who have the rare condition known as monoclonal gammopathy may develop problems with their small blood vessels (capillaries) leading to shock (collapse) which can be fatal, when they use medicines like interferon-beta-1b. See also 4. Possible side effects.
  34. 34. ?
  35. 35. Natalizumab Progressive multifocal leukoencephalopathy (PML) Kleinschmidt-DeMasters,et al. N Engl J Med. 2005 Jul 28;353(4):369-74. 207 cases -1st February 2012 44 (21%) died 163 (79%) alive Mild disability – 10% Moderate disability – 50% Severe disability – 40% 5% NAbs – infusion reactions
  36. 36. Natalizumab PML risk stratification tool Anti-JC virus antibody status Negative Positive Prior immunosuppressant use Natalizumab treatment >2 Years Natalizumab treatment >2 Years No Yes No Yes No Yes Lowest Highest Relative PML Risk < 1 in 10,000 1 in 941 in 256 1 in 6681 in 1887 Mitoxantrone Azathioprine Methotrexate Cyclophosphamide Mycophenolate Cladribine Rituximab Etc.
  37. 37. PML risk estimates for anti-JCV antibody index thresholds were calculated based on the current PML risk stratification algorithm (September 2012) and predicted probabilities (using data from patients with no prior IS use: 2242 non-PML patients and 51 patients who developed PML using all available anti-JCV antibody index data at least 6 months prior to PML diagnosis) for the population at or below that particular index (0.9−1.5) and for the population above an index of 1.5. For index thresholds below 0.9, patient numbers were insufficient to allow for calculation of risk estimates. Anti-JCV antibody index values may differentiate PML risk for those with no prior immunosuppression Index 1−24 months ≤0.9 0.1 (0, 0.41) ≤1.1 0.1 (0, 0.34) ≤1.3 0.1 (0.01, 0.39) ≤1.5 0.1 (0.03, 0.42) >1.5 1.0 (0.64, 1.41) 46 PML risk estimates (95% CI) per 1000 patients with no prior IS use Plavina T et al. Poster DX51, CMSC May 29–June 1 2013, Orlando, USA; Ticho B. et al, Presented at ENS, June 8–11 2013, Barcelona, Spain O228. 46 25−48 months 49−72 months 0.3 (0.04, 1.13) 0.4 (0.01, 2.15) 0.7 (0.21, 1.53) 0.7 (0.08, 2.34) 1.0 (0.48, 1.98) 1.2 (0.31, 2.94) 1.2 (0.64, 2.15) 1.3 (0.41, 2.96) 8.1 (6.64, 9.80) 8.5 (6.22, 11.38)
  38. 38. Predicting autoimmunity following treatment of MS with alemtuzumab • 30% of alemtuzumab-treated pts develop autoimmune side-effects (primarily thyroid disease and idiopathic thrombocytopenia) • Aim: To define predictive factors for autoimmune side-effects • Sera of 141 pts screened at baseline for 8 different cytokines/chemokines A combined IL-21/IL-7 test on pre-treatment serum may be useful to identify patients at low risk of developing autoimmunity following treatment with alemtuzumab Jones JL, et al. ECTRIMS 2011, Amsterdam. P1009 Sensitivity NPV Specificity PPV IL-21 alone 81 84 70 66 IL-7 alone 76 76 54 54 CCL21 alone 63 65 49 47 IL-21 or IL-7 98 97 41 55 IL-21 OR IL-7 OR CCL21 98 91 12 45 Given that pts may elect to receive treatment based on results of this test – most weight given to minimizing false negative results. Combining IL-21 and IL-7 into a single test offers improved test accuracy over IL-21 alone. CCL21 did not improve test accuracy 0 10 20 30 40 IL-7 Autoimmunity No autoimmunity 0 500 1000 1500 IL-21 1.0 Sensitivity 0.8 0.6 0.4 0.2 0.0 0.0 0.2 0.4 0.6 0.8 1.0 1.0 Sensitivity 0.8 0.6 0.4 0.2 0.0 0.0 0.2 0.4 0.6 0.8 1.0 1-Specificity IL-21 and IL-7 levels in sera of pts who did or did not develop autoimmunity Receiver operating characteristic (ROC) curves
  39. 39. Neurology 2012;78(Suppl.): [S41.006]
  40. 40. Anti-natalizumab Antibodies Number of Patients at Risk Placebo Antibody Negative Transiently Positive Persistently Positive 315 568 20 37 296 550 19 32 283 538 18 26 264 526 16 25 248 506 16 24 240 487 16 22 229 480 15 22 216 470 14 19 208 460 14 16 200 449 14 15 Weeks 0.0 0.1 0.2 0.3 0.4 0.5 0 12 24 36 48 60 72 84 96 108 120 29% Placebo 17% Antibody Negative 17% Transiently Antibody Positive 34%Persistently Antibody Positive CumulativeProportionofPatients withSustainedDisability Progression(EDSS) *,† *p ≤0.05 vs. antibody-negative patients †p=0.66 vs. placebo Number of Patients at Risk Placebo Antibody Negative Transiently Positive Persistently Positive 315 568 20 37 296 550 19 32 283 538 18 26 264 526 16 25 248 506 16 24 240 487 16 22 229 480 15 22 216 470 14 19 208 460 14 16 200 449 14 15 Weeks 0.0 0.1 0.2 0.3 0.4 0.5 0 12 24 36 48 60 72 84 96 108 120 29% Placebo 17% Antibody Negative 17% Transiently Antibody Positive 34%Persistently Antibody Positive CumulativeProportionofPatients withSustainedDisability Progression(EDSS) *,† *p ≤0.05 vs. antibody-negative patients †p=0.66 vs. placebo 0.73 0.22 0.16 0.48* 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 AdjustedAnnualizedRelapseRate(95%CI) Placebo (n=315) Antibody Negative (n=568) Transiently Antibody Positive ( n=20) Persistently Antibody Positive (n=37) *p=0.009 vs. antibody-negative patients 0.73 0.22 0.16 0.48* 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 AdjustedAnnualizedRelapseRate(95%CI) Placebo (n=315) Antibody Negative (n=568) Transiently Antibody Positive ( n=20) Persistently Antibody Positive (n=37) *p=0.009 vs. antibody-negative patients Calabresi et al, Neurol 2007 Impact of anti-natalizumab antibodies on . . . . . Annualized relapse rate Progressive disability
  41. 41. Natalizumab infusion reactions • Acute hypersensitivity reactions are well-recognized • Generalized urticaria, dizziness, fever, rash, rigors, pruritus, nausea, flushing, dyspnea, chest pain • Onset generally during or within 1 hour of second infusion • Incidence ~4% • severe anaphylactic/anaphylactoid reactions <1% • Most reactions are associated with anti-natalizumab antibodies • Treatment: • immediate and permanent cessation of natalizumab • antihistamines Rudick et al, NEJM 2006
  42. 42. Monitoring effect of therapeutic interventions
  43. 43. Reduced efficacy due to NAbs – systematic review Farrell & Giovannoni, Multiple Sclerosis 2007; 13: 567-577.
  44. 44. Clinical importance of neutralising antibodies against interferon beta in patients with relapsing-remitting multiple sclerosis Sorensen et al. Lancet 2003; 362: 1184–91.
  45. 45. Jacob Elkins, James Sheridan, Lakshmi Amaravadi, Katherine Riester, Gilmore O’Neill Neurology 2012;78(Suppl.): S31.004
  46. 46. Prognostic markers
  47. 47. Intrathecal synthesis of IgG Images courtesy of Alastair Compston and Ed Thompson. Kabat et al. J Clin Invest. 1942 Sep;21(5):571-7. Carl Lange – Colloidal Gold Curve Isoelectric focusing with immunfixation
  48. 48. Petzold, J Neurol Sci. 2005 Jun 15;233(1-2):183-98.
  49. 49. Conclusion • Diagnostic/prognostic biomarkers • Intrathecal OCBs • IgG Index • Pharmacovigilance • Baseline screening • Monoclonal gammaopathy (IFNbeta) • Serology – VZV, JCV (immunosuppression) • Monitoring • FBC, LFTs, U&E, TFTs • Monthly platelets and possibly urine (alemtuzmab) • Serology – JCV (natalizumab) • CD56-bright cells (daclizumab) • NABs (IFNbeta and natalizumab) • Potential surrogate treatment markers • CSF neurofilament levels • Potential future baseline response markers • Type 1 interferon signature • PBMC transcriptomic profiles
  50. 50. Acknowledgements • Giovannoni • Sharmilee Gnanapavan • David Baker • Gareth Pryce • Sarah Al-Izki • Sam Jackson • Katie Lidster • Yuti Chernajovsky • Alex Annenkov • Anne Rigby • Michelle Sclanders • Larry Steinman • Peggy Ho • Charles ffrench-Constant • Robin Franklin • Siddharthan Chandran • David Hampton • Ian Duncan • Sam Jackson • Peter Calabresi • Avi Nath • Raj Kapoor • John Zajicek • Doug Brown • UK MS Clinical Trial Network • BioMS • Co-investigators • NABINMS • Affirm study • Care MS 1 & 2 studies • Select trial
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