Multiple Sclerosis Update on Ongoing Research at the Jacobs MS Center

1. Multiple SclerosisUpdate on Ongoing Research at the Jacobs MS Center Bianca Weinstock-Guttman, MD, Professor of Neurology SUNY University at Buffalo, UBMD Neurology

2. The Atlas of MS2013 • The Atlas of MS 2013 updates the information that was collected in 2008 on: • global epidemiology of MS • resources to diagnose • inform • treat • rehabilitate • support and provide services to people with MS around the world.

3. KEY FINDINGS • The estimated number of people with MS has increased from 2.1 million in 2008 to 2.3 million in 2013. • This finding reinforces the conclusions of the published epidemiological literature. • MS is found in every region of the world. • The 2:1 ratio of women to men with MS has not changed significantly since 2008.

4. Atlas of MS2013

5. More research is needed • In relation to quality of life and experiences of people with MS. • To measure the indirect costs of MS. • To understand sources and causes of inequalities in access to support, health care services and therapies. • To monitor MS and related disorders through epidemiological studies and the establishment of registries.

6. Getting to What Matters to MS Patients Environment Tissue Injury Genetics Infectious Agents Healthy Brain Disease Progression

7. Types of Multiple Sclerosis

8. Environmental Factors • Epstein Barr Virus • Vitamin D • Smoking • Lipids

9. Cholesterol • High cholesterol is a known risk factor for heart disease and stroke • HDL – High density lipoprotein “Good” cholesterol • LDL – Low density lipoprotein “Bad” cholesterol

10. Cholesterol • Cholesterol is essential • 75% of cholesterol is made in the liver • Remainder from the diet • Cholesterol is recycled and re-used • Cholesterol is the chemical building block for hormones like cortisol, estrogen, progesterone, testosterone

11. Cholesterol in the Brain • The brain represents 2% of body weight • Contains 25% of body cholesterol! • 70% of brain cholesterol is in myelin

12. Mechanisms of Cholesterol Action in MS • Effects on brain vasculature • Effects on inflammation • Effects on neurodegeneration • Effects on vitamin D • Oxysterols, which are cholesterol metabolites, have potent effects on the immune system

14. Cholesterol and Vitamin D

16. HDL Cholesterol Affects Vitamin D • Higher HDL is associated with vitamin D sufficiency

18. Cholesterol & New Lesions • Higher cholesterol is associated with formation of new lesions

20. Cholesterol & Optic Neuritis • Higher cholesterol is associated with poorer recovery from optic neuritis

21. Lipoprotein Particles • Lipids • Cholesterol • Proteins – • Lipoproteins • Enzymes

22. Conclusions • The role of cholesterol and lipids in MS is not well understood • Cholesterol may have effects on MS disease progression • Careful study is needed because the cholesterol pathway is complex and inter-connected with other physiological functions.

23. Disease-Modifying Therapies in Late Stages of Clinical Development

24. Meaningful impact Disease course MRI ? > efficacy than ABCR ? Window of opportunity Convenience Treatment Decisions: Considering Benefits and Risks Benefits Risks Short-term safety Long-term safety Pregnancy issues Many unknowns ABCR = Avonex, Betaseron, Copaxone, or Rebif

25. Pediatric Network Research Priorities • Epidemiology • Genetics • Microbioma • Imaging • Neuropsychology • Treatment

26. Aging with MS • MS beyond age 60 • Knowledge and Understanding for Clinicians and patients • Outcome – Disability (EDSS) and Psychosocial Well-being (LIFEware) • DMT Safety and Tolerability • Discontinuation

27. Aging with MS • In addition to demographics (DOB education and marital status) Emphasis • Comorbid conditions • Insurance • Quality of Life - Patient-reported activities of daily living: Get up from sofa, climbing stairs, standing, driving, vision, fatigue • QoL – Psychosocial: Mood (depression, anxiety, stress, loneliness, guilt, life satisfaction)

28. Aging with MS – Potential Sample & Funding • Secure funding to conduct an additional • $100.00 Site Compensation for each patient ($ 50,000) • Multi-Site Start-up ($2,000 to 5,000) • Project Manager (PT 20,000) • Structured similar to PR Study - infrastructure in place • Projected funding need = $125,000 • Blood and MRI – add to budget

29. Oligodendrocyte progenitor cells for the treatment of chronic progressive multiple sclerosis PI: Burk Jubelt Co-PIs: Steve Goldman Andrew Goodman Bianca Weinstock-Guttman

30. Goldman et al., Science, 2012

31. 12 weeks 20 weeks NF MBP hNuclei 35 weeks

32. Goal: To establish a human OPC-based therapeutic for the treatment for secondary progressive multiple sclerosis Choice of target: Secondary progressive MS Hypothesis: OPCs transplanted to patients with immunologically quiescent secondary progressive multiple sclerosis will experience stabilized/improved neurological function, including cognition and mobility via functional cell-mediated effects

33. Fig. 1 Sites of neural stem cell direct implantation. N. Gupta et al., Sci Transl Med 2012;4:155ra137-155ra137 Published by AAAS

34. Acknowledgments Collaborators Support National MS Society Department of Defense NYSTEM NIH Biogen Idec Novartis Genzyme& Sanofi TEVA Questcor Acorda • Murali Ramanathan, PhD • Robert Zivadinov, MD, PhD • Ralph Benedict, PhD • Richard Browne, PhD • Barbara Teter, PhD • David Hojnacki, MD • Channa Kolb, MD

35. Training my body = training my brain!