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5th UCLP MS Research Day Curing MS
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5th UCLP MS Research Day Curing MS

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  • 1. Why haven’t we cured MS yet? Gavin Giovannoni Barts and The London
  • 2. To cure MS do we need to know the cause? EBV Vitamin D SmokingGenes
  • 3. We work on the hypothesis that MS is an autoimmune disease. Multiple Sclerosis Environ- ment Genes
  • 4. The autoimmune hypothesis Multiple Sclerosis Environ- ment Genes
  • 5. What does a cure mean? Disability Time
  • 6. delayed worsening1 stabilised2 improved function3 recovered function4 What does a cure mean?
  • 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. 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. 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. 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. The autoimmune hypothesis Multiple Sclerosis Environ- ment Genes
  • 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. Curing animal MS
  • 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. 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. Control Multiple sclerosis Moving the target: end-organ damage
  • 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. 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. 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.