Stem cell therapy for children with Pelizaeus-Merzbacher disease

Written on Wednesday 24 April 2013

Pelizaeus-Merzbacher disease is a rare leukodystrophy due to a mutation in the proteolipid protein 1 gene. In this disease, the deficient myelin cells cannot myelinate axons inducing a global neurological impairment. The HuCNS-SCs stem cells of the central nervous system originating from a human donor can develop into myelin cells when transplanted in a hypomyelinating mouse model and confer structurally normal myelin.

A clinical trial aiming at testing the safety of these cells and detecting signs of myelin formation after their engraftment in humans was developed.


Cells were implanted surgically into the white matter of 4 boys suffering from an early severe form of PMD. During 9 months, the treated kids were given immunosuppressive therapy in order to prevent graft rejection. Regular neurological evaluations, developmental assessments, MRI and magnetic resonance spectroscopy including DTI were performed before and after treatment.

The neurological procedure, the immunosuppression regimen and the HUCNS-SCs cell transplantation were well tolerated. Modest improvements in neurological function were observed in 3 of the treated children. Moreover, no clinical or radiological adverse events were induced by the donor cells. The MRI and magnetic resonance spectroscopy tests showed results consistent with myelination in the transplanted region.

These findings indicate HuCNS-SCs cells are safe in treated patients. In addition, the MRI results suggest durable cell engraftment and myelin deriving from donor in the white matter of the transplanted patient.

Disease: Pelizaeus-Merzbacher disease (PMD).
Type of study: clinical trial.
Subjects: children with the conatal form of PMD.
Laboratory: Dr David Rowitch, department of Neurosurgery, University of California, San Francisco, CA, United States of America.





This study has merit to have been conducted after 30 years of research on myelin and it shows:

  • the safety of the treatment over a short period which is important.
  • a discrete effect on the development of the treated children. At this age, some children progress, but it is unclear whether this effect is due to the treatment or to the natural course of the disease.
  • very discrete MRI changes that only suggest a possible remyelination. Although the methodology used in this study is standard, the DTI technique does not directly study myelin but water movements along axons. We must remain very cautious in interpreting the results.

Cell therapy is a promising approach and this study should be recognized. However, issues dealing with this type of therapy should be acknowledged:

  • The injected cells may have beneficial effects, not directly (in this case remyelinating) but indirectly (nutritional effect) and transiently like in Parkinson’s or Huntington disease.
  • The injected cells may take the phenotype of the sick cells of the patient.
  • The fate of transplanted cells and their survival remains unclear
  • The real therapeutic effect for chronic diseases is difficult to evaluate without studies against placebo.
  • Patients are subjected to short term immunosuppressive therapy. The effect of such immunosuppression in the long run is far from being negligible.

Pr. Patrick Aubourg
Bicêtre Hospital, Le Kremlin-Bicêtre, France

Pr. Odile Boespflug-Tanguy
Robert-Debré Hospital, Paris, France


Reply from the investigators

We are grateful to Drs. Boespflug-Tanguy and Aubourg for their insightful comments regarding our manuscript describing the neural stem cell transplantation in children with Pelizaeus-Merzbacher disease (PMD). The last few decades have witnessed a dramatic increase in our understanding of oligodendrocyte developmental biology, and the use of neural progenitor cells for treating disorders of myelin formation. The nature of Pelizaeus-Merzbacher disease, in some respects, makes it an ideal candidate for human studies. But as Drs. Boespflug-Tanguy and Aubourg point out, there are also complex issues that affect clinical trial design and interpretation of the data, so we must maintain a conservative attitude regarding the therapeutic potential of neural progenitor cell transplantation for early-severe forms of PMD.

We were encouraged to find that the transplantation procedure and the cells themselves appear to be safe and that we saw signs by special MRI techniques indicating cell engraftment, and the potential for myelin production. This is also consistent with preclinical data from rodent experiments where myelin production was clearly demonstrated. The MRI findings we used in the human subjects are widely accepted as indicating myelin formation, but do not prove the presence of myelin in the same way that we could do with a laboratory study and histological analysis. An important question in future clinical trials is whether these MRI techniques are an acceptable surrogate for myelin production.

Our study was designed to examine safety, rather than efficacy, and so many important issues such as control groups, placebo procedures, and, whether the most severe form of PMD is the optimal condition to demonstrate clinical benefit was not directly addressed. We anticipate the points raised by Dr. Aubourg will be incorporated in future clinical trials, and we look forward to working with experts on the optimal design of a follow-on study. Regarding the issue of immunosuppression, we found that MRI signals in region of the transplant persisted after cessation of immunosuppression and were not associated with signs of rejection of the donor cells. Thus, we do not see evidence in our study of a beneficial effect of immunosuppressive drugs themselves. However, this may be another very important question for future study.

In the field, there is rapid progress in developing stem cell transplantation for myelin diseases, as well as other neurological disorders. We expect that through a deliberate process of clinical testing, first with safety and then measurement of efficacy, the optimal cell-based approach to use for PMD and other leukodystrophies.

We would like to thank the families for their support of ELA in Europe and the PMD Foundation in the United States, who have shown encouragement and support for the important, yet challenging, initial studies to begin to translate therapies for the benefit of leukodystrophy patients.

Yours sincerely,

David H. Rowitch, MD, PhD
Nalin Gupta, MD, PhD
University of California  San Francisco

Stephen Huhn, MD
StemCells, Inc.

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