Mark Steven Freedman, MD
Senior Scientist, Neuroscience, Ottawa Hospital Research Institute
Professor of Medicine (Neurology), University of Ottawa
Director, Multiple Sclerosis Research Unit, The Ottawa Hospital-General CampusResearch Interests
- Neuroimmunology as applied to the study of MS
- Clinical MS research
- Therapeutic trials in MS
- ASCT as a potential treatment for MS
- The role of gamma delta T cells in the pathogenesis of MS
- The role of cytokines in MS disease progression or response to therapy
Multiple sclerosis research has been exploding in recent years with the advent of new tools both in neuroscience and immunology to further our understanding of the disease. My own focus of research has been concentrated in 3 areas:
With 2 PhD students, one nearly finished and the other nearly starting, this is still an active area. Both projects revolve around my focus for the past decade on the innate immune system and in particular, gd T cells . Work done mostly by Zhihong Chen has examined a unique feature of these cells to cytolyse cells using the mechanism of antibody-dependent cell cytotoxicity via their Fc receptors. His work has revealed that patients particularly with the progressive phase of their illness display the greatest number of Fc bearing gd T cells. Research has revealed also a number of antibodies to myelin that may be playing a role at this stage and our hypothesis is that these antibodies can direct gd T cells to injure oligodendrocytes. In collaboration with Dr. Jack Antel at the MNI, Zhihong has shown this to be the case.
In a separate project together with Peter Stys, Jennifer Beveridge is concentrating on a model of in vitro demyelination that Peter and I developed together, wherein we can inject cells generated in my laboratory directly into a rat optic nerve and watch how they cause damage to myelin and axons. Jennifer has chosen to move to Calgary for the first couple of years of this project and then to return here for the latter part to work with the immune cells.
Clinical Investigator-Driven Research
Together with Harry Atkins, our work on the Canadian bone marrow transplantation has gained international notoriety. Our observations have been seminal and has generated many new observations not only clinically, but through the vast imaging and immunological monitoring developed in conjunction with our colleagues, to follow this unique group of patients who undergo autologous stem cell transplantation following complete immune ablation. We have recently received a new grant from the MS Foundation to examine, in particular, some of our observations that the disease is not only halted following this treatment, but some patients make some miraculous recovery, suggesting repair of the CNS. We have hypothesized several mechanisms that might explain this phenomenon and have laid out a series of studies to help substantiate these.
In a separate and new venture, Harry and I are working on developing a new technology to try on our more progressive patients; that of mesenchymal stem cell (MSC) transplantation. These cells would not require a complete immune ablation such that patients will be spared the morbidity of that procedure. Together with a world renowned scientist in Montreal for his work on growing MSC we hope to have a viable protocol that can be brought to clinical testing within the year.
Clinical Industry-Driven Research
It would appear that there is no end to new studies with a vast array of new agents that bring to the table less morbidity and novel targeted immune therapies, from small molecules aimed at controlling either the expression of a receptor or the release of cytokines, to more focused monoclonal antibody treatments. Studies are now focusing on all phases of MS including the more later stages with agents that might be capable of regeneration or repair. As a member of many steering committees and consultant to several companies, I have been assisting in the development of these trials and hope to keep TOH at the forefront of MS research.
Freedman MS. Editor, Special Issue. Clinical Trends in Neurology. June 2005.
Freedman MS (editor). Advances in Neurology. Multiple Sclerosis and Demyelinating Diseases. Published by Lippincott Williams & Wilkins. Volume 98. 2006.
Atkins H and M Freedman. Chapter 19 "Immunosuppression", in: Cook S (ed), Handbook of Multiple Sclerosis, Taylor & Francis, New York, pages 423-441, 2006.
Freedman MS. Editor, Special Issue. Clinical Trends in Neurology. June 2005.
Atkins H, Freedman MS. Immunosuppression, Handbook of Multiple Sclerosis 4th Edition, Marcel Dekkler Inc. Cook (ed.) 2006: 19:423-442.
Freedman MS, Thompson EJ, Deisenhammer F, Giovannoni F, Grimsley G, Keir G, Ohman S, Racke MK, Sharief M, Sindic CJM. Special Report: Recommended standard of cerebrospinal fluid analysis in the diagnosis of multiple sclerosis: A Consensus Statement. Arch Neurol. 2005 June;62(6):865-70.
Chen JT, Collins DL, Freedman, MS, Atkins HL,and Arnold DL, the Canadian MS/BMT Study Group, Arnold DL. Local magnetization transfer ratio signal inhomogeneity is related to subsequent change in MTR in lesions and normal-appearing white-matter of multiple sclerosis patients. NeuroImage. 2005 May 1;25(4):1272-1278.
Freedman MS, Francis GS, Sanders EACM, Rice GPA, O'Connor P, Comi G, Duquette P, Metz L, Murray TJ, Bouchard J-P, Abramsky O, Pelletier J, O'Brien F, for the OWIMS Study Group and UBC MS/MRI Research Group. Randomized study of one-weekly interferon -1a therapy in relapsing multiple sclerosis: Three year data from the OWIMS Study. Multiple Scler. 2005;11:41-45.
McFarland H, Barkhof F, Calabresi P, Clanet M, Cohen J, Cutter G, Freedman MS, Lublin F, Metz L, Miller A, Montalban X, Noseworthy J, O'Connor P, Panitch H, Petkau J, Polman C, Reingold S, Schwid S, Thompson A, Wolinsky J. On behalf of the National MS Society Advisory Committee on Clinical Trials of New Agents in MS. The future of MS therapies: redesigning MS clinical trials in a new therapeutic era. Multiple Scler. 2005;11:669-676.
Freedman MS. Defining the standards of multiple sclerosis research. Clinical Trends in Neurology. 1:20-24. June 2005.
Francis GS, Rice GP, Alsop JC; PRISMS Study Group. Interferon beta-1a in MS: results following development of neutralizing antibodies in PRISMS. Neurology. 2005;July 12;65(1):48-55. (M. Freedman is a member of the PRISMS Study Group.)
Gold R, Rieckmann P, Chang P, Abdalla J; PRISMS Study Group. The long-term safety and tolerability of high-dose interferon beta-1a in relapsing-remitting multiple sclerosis: 4-year data from the PRISMS study. Eur J Neurol. 2005;Aug;12(8):649-56. (M. Freedman is a member of the PRISMS Study Group.)
Oger J, Francis G, Chang P; On behalf of the PRISMS Study Group. Prospective assessment of changing from placebo to IFN beta-1a in relapsing MS: The PRISMS study. (M.S. Freedman is a member of the PRISMS Study Group.) J Neurol Sci. 2005;Oct 15;237(1-2):45-52.
Petkau AJ, White RA, Ebers GC, Reder AT, Sibley WA, Lublin FD, Paty DW; IFNB Multiple Sclerosis Study Group. Longitudinal analyses of the effects of neutralizing antibodies on interferon beta-1b in relapsing-remitting multiple sclerosis. Mult Scler. 2004;Apr;10(2):126-38. (M. Freedman is a member of the IFNB MS Study Group.)
Banwell BL, Reder AT, Krupp LB, Tenembaum S, Eraksoy M, Boiko A, Pohl D, Freedman MS, Schelensky L and Antonijevic I. A Multicenter review of the safety and tolerability of interferon beta-1b in pediatric multiple sclerosis" by, based on the data collected and discussed in the expert group. Neurology. 2006. 66:472-476.
Kinkel RP, Kollman C. O'Connor P, Murray TJ, Simon J, Arnold D, Bakshi R, Weinstock-Gutman B, Brod S, Cooper J, Duquette P, Eggenberger E, Felton W, Fox R, Freedman MS, Galetta S, Goodman A, Guarnaccia J, Hashimoto S, Horowitz S, Javerbaum J, Kasper L, Kaufman M, Kerson L, Mass M, Rammohan K, Reiss M, Rolak L, Rose J, Scott T, Selhorst J, Shin R, Smith C, Stuart W, Thurston S, Wall M. The CHAMPIONS Investigators Group. (M.S. Freedman is a member of CHAMPIONS Investigator Group.) Neurology. 2006;66(5)678-84.
O'Connor PW, Li D, Freedman MS, Bar-Or A, Rice GPA, Confavreux C, Paty DW, Stewart JA, Scheyer R. On behalf of the Teriflunomide Multiple Sclerosis Trial Group and the University of British Columbia MS/MRI Research Group. A phase II study of the safety and efficacy of Teriflunomide in multiple sclerosis with relapses. Neurology. 2006;66(6):894-900.
O'Connor KC, McLaughlin KA, De Jager PL, Chitnis T, Bettelli E, Xu, C, Robinson WH, Cherry SV, Bar-Or, A, Banwell B, Fukaura H, Tenembaum S, Wong SJ, Tavakoli NP, Idrissova Z, Viglietta V, Rostasy K, Pohl D, Dale RC, Freedman MS, Steinman L, Khoury S, Weiner H, Kuchroo VK, Hafler DA, Wucherpfennig KW. Self-assembling antigen tetramers permit discrimination of autoantibodies to folded and denatured self-antigens in demyelinating disease. 2006. Manuscript submitted.