Trialing bone marrow stem cells in human spinal cord injury

Release date: 27-Apr-2011

Organisation: Cairo University and Kaser Al-Aini Hospital, Cairo, Egypt

Background It is of course always encouraging to hear about bench-to-bedside developments in the use of cell-based transplants for spinal cord injury. The hope is that transplanted cells might be able to replace lost neurons, support or guide growing axons, bridge the injury site or replace lost myelin, and thus lead to improvements in function.  With a lot of potential candidates to choose from Cairo University researchers decided to trial human bone marrow mesenchymal cells (BMSCs) in the human spinal cord. We have all heard about how neural “stem” cells can be prepared from embryonic tissue, but bone marrow is perhaps best known as a source of stem cells for patients with acute myeloid leukemia. Nonetheless, it has been argued that BMSCs offer advantages for cell-based spinal cord injury therapies on the grounds that they are:
•    Easily accessible and readily expanded in culture;
•    Able to migrate into and infiltrate the damaged spinal cord tissue; 
•    When autologous (ie the donor and recipient/host are the same person), cells are compatible with the host immune system, overcoming rejection issues;
•    Exempt from the controversy surrounding embryonic stem cells, thus offering an ethically acceptable cell therapy approach. 

The Study The Cairo team took BMSCs from 43 patients with chronic spinal cord injury (at cervical and thoracic levels) and injected them into the fluid filled cavity (CSF) surrounding the spinal cord at the lumbar level.  A further 20 patients acted as controls, receiving a similar rehabilitation program but no cell injections. While this was not a randomised clinical trial in the strictest sense, the study was well designed and the findings add significantly to previous observations made in isolated cases and smaller human trials. The cells were injected at monthly intervals, for six months, and the results assessed 12 months after the cell injections. The study end points were safety and effectiveness, as determined using physical and electrophysiological tests and clinical observations. Small improvements in movement were seen amongst the treated patients, compared to controls, although assessments of sensation, bladder and bowel function were not different between the two groups. Since the motor changes were minor and patients in both groups showed improvements during the study period, it was difficult to dissect out gains that may have been attributed directly to the transplanted cells and those that resulted from the rehabilitation program. Magnetic resonance imaging (MRI) also was used, but the researchers were unable to shed light on what happened to the transplanted cells after they were injected into the CSF.

Side effects On a cautionary note, one patient in the treatment group, whose spinal cord injury was caused by myelitis, developed a life-threatening viral inflammation of the brain.   Other side effects in the transplanted group included the development of neuropathic pain (56% of patients) and increased muscle tone (spasticity) while no changes in complications occurred amongst the control group.

Comment
Clinicians have been concerned about the risk of cysts caused by bacterial infections and also, the likelihood of transplanted cells forming spinal cord tumours. Kishk and colleagues followed their patients for 12 months and it is of course possible that a longer follow up period may have led to different findings. Therefore, it is too early to say whether other, as yet unknown side effects will emerge over time, or if early side effects will resolve.  

What lessons have been learned from this study? Autologous BMSCs are seen as promising candidates for transplantation in spinal cord repair.  However, the findings of Kishk and colleagues in chronic human spinal cord injury flag important safety concerns.  The Cairo researchers conclude that more studies will be needed before BMSCs can usefully be tested again in the human spinal cord.  Whilst disappointing, it can be difficult to know when a particular therapy is ready for human clinical trials, and even negative findings can be powerful tools for unravelling responses. Kishk’s study indicates that we need more animal studies that test:
•    chronic injuries, to determine the best timing for cell transplants after injury;
•    the dose and duration of cell injections;
•    side effects associated with inflammation, such as pain;
•    differences in cord responses after traumatic versus non traumatic causes of injury.  

Furthermore, to justify large scale commercial investment in human trials, we need advances in: 
•    imaging techniques,  possibly allied to particle labeling of transplanted cells;
•    markers of regeneration and remyelination, preferably using noninvasive approaches;
•    simple physiological tests of autonomic function.

Related studies
Readers who are interested in this topic might like to check out Kwon and colleagues (> more) who looked at the question of how ready a particular therapy is for human trial. The Kwon paper was also reviewed on the Spinal Cord Injury Network website. Also it is sobering to note that a review of 43 studies of BMSC transplants into animals did not translate into a beneficial outcome when tested in patients. A possible explanation involves variable survival of BMSC transplants in the human spinal cord since, in animals, cell survival within the cord was highly variable.

In summary, we have come a long way in establishing what happens to cells when they are transplanted into the spinal cord in animals, but for establishing efficacy in human trials, we need better evidence about how many cells survive in the human cord, for how long, and whether they lead to potential complications.

Jillian M Clark Ph.D.
Post Doctoral Fellow
SASCIRC, Hampstead Rehabilitation Centre, South Australia
Member of the Spinal Cord Injury Network’s Research Development Committee

April 2011

Reference
Kishk, et al. (2010) Case Control Series of Intrathecal Autologous Bone Marrow Mesenchymal Stem Cell Therapy for Chronic Spinal Cord injury. Neurorehabilitation and Neural Repair, 24; 702-708.

Link to abstract - www.ncbi.nlm.nih.gov/pubmed/20660620



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