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NIH Symposium: Challenges & Promise of Cell-Based Therapies
May 6, 2008
Natcher Conference Center
NIH Main Campus, Bethesda, Maryland

Session 1: Neurological Disorders

Moderator: Ronald McKay, Ph.D.; National Institute of Neurological Disorders and Stroke, NIH

Bone-Marrow Derived Stem Cells and Multiple Sclerosis
Mark S. Freedman, M.D., M.Sc.; Ottawa Health Research Institute and the University of Ottawa

Dr. Freedman began by observing that multiple sclerosis (MS) evolves over time in a phasic process; early inflammatory phases precede the neurodegenerative phase that features axonal loss and cortical atrophy. It is postulated that early inflammatory events contribute to this neurodegeneration; there is evidence of axonal loss at the beginning of the inflammatory phase. Therefore, the timing of therapy is critical to prevent disability. The clinical manifestation of disease appears as a clinically-isolated syndrome (CIS) early in the degenerative process, suggesting that a time window exists for early treatment. Nonetheless, treatment of CIS often fails to prevent progression (Kappos L, Lancet 2007;370:389-397). Because some inflammation is associated with the healing process, it is critical to apply an intervention that strikes a balance between "good" and "bad" inflammation. Bone marrow transplants plus autologous stem cell transfer was an initial approach to this issue. This strategy involves the complete removal of the diseased immune system to halt ongoing MS immune-mediated central nervous system (CNS) damage. Purified HSCs are capable of restoring a functional immune system, although the reconstituted immune system will not likely result in the redevelopment of the CNS-directed immune response. However, transplanted stem cells could feasibly induce repair.

Dr. Freedman noted that the data relevant to the fate of transplanted HSCs are quite provocative. Case studies have identified a post-transplant, non-random distribution of cells throughout the brain that suggests that transplanted cells migrate to areas of need (Mezey E, PNAS 2003;100:1364-1369). Moreover, there appears to be an absence of cell fusion (Cogle CR, Lancet 2004;363:1432-1437). It has been hypothesized that these cells may be a source of new brain cells. Although many laboratories are exploring this approach, their techniques vary (Saccardi R, Mult Scler 2006;12:814-823). Although MS represents a variety of disease types, the absolute treatment mortality rate is approximately 5%. A slightly lower mortality rate is observed in secondary-to-progressive MS cases. This lower mortality has been attributed to avoiding recent transplantation in patients who have high Expanded Disability Status Scale (EDSS) scores and screening for comorbidities that confer added risk of transplant-related infection or other side effects. (The EDSS is a composite scale that assesses a range of functional attributes [visual, brainstem, pyramidal, cerebellar, sensory, mental, and bowel/bladder]). Younger patients transplanted within five years of diagnosis show a greater chance of survival, and an analysis of available studies also suggests evidence of progression in the absence of inflammation.

Results from a recent BMT trial in patients with MS indicated no treatment failures within 65+ months of follow-up and no recorded relapses in any patient. Three patients have met the definition of sustained progression, and no gadolinium-enhancing lesion has been observed to date in any patient. Improvements are often seen after as long as two years in areas such as pyramidal and cerebellar function. It is unclear why this delayed repair is observed, although stem cells may be responsible. Using imaging techniques, changes in individual lesions can be measured over time, and changes observed thusly parallel pathologic changes. In preliminary analyses, patients who had more inflammation upon beginning treatment were more likely to benefit. Immunological analyses also revealed that Th17 cells were greatly reduced one year after treatment.

Concerns and limitations raised by this approach include the following:

  • How to tell whether the axons are still reparable (e.g., whether they will accept to be remyelinated)
  • How to determine expectations of the transplanted cells (e.g., to enact or assist in repair or to serve as a source of new renewable CNS cells)
  • What to do about the status of CNS inflammation at the time of transplant (Some degree of inflammation is necessary for remyelination and repair; transplanted cells may actually require the inflammatory environment [Foote AK and Blakemore WF. Brain 2005;128:528-539]).
  • How to determine which patients should receive these interventions and when they should receive them
  • How to track transplanted cells and prove that they are migrating to the CNS

These concerns have led to the consideration of chronic "cyclic" therapeutic approaches that allow repair to occur.

In conclusion, Dr. Freedman noted that immunoablation with autologous HSC transplantation is a viable treatment modality for MS patients with early, aggressive disease. Patient selection is critical to maximize therapeutic response and minimize toxicity. Conditioning regimens continue to improve in terms of reducing morbidity and mortality, and delayed recovery in some patients suggests endogenous repair.


One attendee asked about the hypothesis that drove the clinical study described in the presentation. Dr. Freedman noted that the study was designed to assess whether the immune system could be "rebooted" at the earliest signs of MS. The trial was not designed to assess improvement, per se, although some tissue repair was observed.

Another participant inquired about the absence of Th17 cells. Dr. Freedman noted that no Th17 cells have been observed in the patients studied, although the population is somewhat unusual in that they have delayed recovery.