5th UCLP MS Research Day Curing MS

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5th UCLP MS Research Day Curing MS

  1. 1. Why haven’t we cured MS yet? Gavin Giovannoni Barts and The London
  2. 2. To cure MS do we need to know the cause? EBV Vitamin D SmokingGenes
  3. 3. We work on the hypothesis that MS is an autoimmune disease. Multiple Sclerosis Environ- ment Genes
  4. 4. The autoimmune hypothesis Multiple Sclerosis Environ- ment Genes
  5. 5. What does a cure mean? Disability Time
  6. 6. delayed worsening1 stabilised2 improved function3 recovered function4 What does a cure mean?
  7. 7. MRI Lesions 1st clinical attack Time (Years) Asymptomatic disease Inflammation Brain volume loss Nerve cell loss DiseaseSeverity SPMSRRMS 1st MRI lesion Relapses CISRIS 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
  8. 8. MRI Lesions 1st clinical attack Time (Years) Asymptomatic disease Inflammation Brain volume loss Nerve cell loss DiseaseSeverity SPMSRRMS 1st MRI lesion Relapses CISRIS 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
  9. 9. 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
  10. 10. 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
  11. 11. The autoimmune hypothesis Multiple Sclerosis Environ- ment Genes
  12. 12. 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
  13. 13. Curing animal MS
  14. 14. 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
  15. 15. 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
  16. 16. Control Multiple sclerosis Moving the target: end-organ damage
  17. 17. 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
  18. 18. Have we got it wrong? EBV Vitamin D SmokingGenes Multiple Sclerosis Environ -ment Genes Is MS due to a virus? Charcot Project INSPIRE Trial (Raltegravir) Etc. etc. etc.
  19. 19. 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.

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