Cells are implanted into the damaged spinal cord by direct injection. There are several variables to consider in the development of a safe injection method. Transplant injections have the potential to create damage to preserved spinal tissue in several ways and associated injury must be minimized. The most damaging injections are those of large volumes, delivered rapidly, with poor control over motion of the needle and tissue interface . In the clinical environment, it is important to consider all contingencies that might add risk during the cellular transplantation because unpredictable events such as, for example, electrical power failure or anesthetic emergencies, including cardiopulmonary instability, although uncommon, do occur. Therefore, the ability to terminate the injection and exit the spinal cord rapidly is necessary. A rigid needle within spinal cord tissue can cause serious injury if there is loss of control of the position of the needle because of operator error, injection device dysfunction, or inadvertent patient motion. Currently, there are three main approaches to make spinal cord injections: free hand needle injections, fixed platform injections, and floating cannula injections [47,48]. Each method has specific merits and limitations. We currently use a fixed platform injection apparatus.
Selecting the optimal clinical cell dose is a challenging task because of the complex effects of cells compared to more conventional drugs. For example, after most cell injections, some cells will die and engender some degree of inflammation. Thus, both beneficial and harmful events may occur simultaneously after transplantation. The best cell dose is a function of the final result in the tissue and may not be based solely on a single tissue effect. There is a limited ability to monitor toxicological endpoints in SCI patients receiving cell transplants other than worsening of the neurological injury density or level. Complications of SCI such as neuropathic pain and spasticity occur to some extent in most patients and linking these endpoints to the cell dose may be difficult. The formation of abnormal tissue or tumors may occur independent of the cell dose. In our IND development, we have focused on learning the maximum tolerated dose that can be delivered to the spinal cord in animals and not cause additional injury that is evident by clinical examination, neurophysiology, postinjection MRI, or histology. We found that the minipig SCI model was very useful for dose tolerance studies because of its human-like neural axis dimensions. On the basis of large animal testing, we determined a well tolerated dose at which to initiate the study and successive larger doses that may exert a superior therapeutic effect.
In our current study, the most important outcomes are the feasibility of the autologous transplant strategy and the safety of the procedures and cellular implant. Impairment of residual neurological function could occur as a result of the surgical implantation procedure or because of the biological effect of the cell transplant. In patients with complete thoracic SCI, such changes are measured using sensory testing, with the neurological level as the endpoint. This level is defined as the last at which sensory perception is normal on both sides. The outcome measures we are utilizing are listed in Table 3 [5–7].
It is desirable to have clinical tests that allow the effect of cell implantation to be followed longitudinally, especially to determine cell survival and biological activity. This is important because a clear impact on neurological recovery may not occur with cell grafts alone and will likely require future combination therapies. The paucity of surrogate markers is not unique to Schwann cell transplantation, but is a general problem facing the CNS cell therapy field. The doses of transplanted cells are relatively small compared with the overall cell death that occurs after SCI, potentially masking the ability to detect Schwann-cell-specific markers of cell death and survival. For Schwann cells, the issue is further complicated because of the fact that endogenous Schwann cells enter the regions of SCI and may have similar biological activity. Because allografts require immune suppressive drugs to avoid cellular rejection, formation of antiallograft antibodies is a useful biomarker that is not available for autografts to determine a definite host response. It is likely that progress in this area will require the development of well tolerated molecular markers that the transplanted cells can uniquely express and which do not impair their biological activity in the long term.
Autologous Schwann cell transplantation is a reasonable treatment approach to the repair of spinal cord injuries based on the role of Schwann cells in peripheral nerve repair, the endogenous Schwann cell's response to spinal cord injury, and the feasibility of preparing and delivering the cells. More clinical experience is required to determine the safety and efficacy. It is probable that future studies will combine Schwann cell transplantation with additional therapies to amplify the reparative effects.
Papers of particular interest, published within the annual period of review, have been highlighted as:
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An important update on FDA's expectations for preclinical data to support cellular therapy clinical trials.
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The first reported study of cell therapy in acute spinal cord injury.
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An important multicentre prospective study that provides baseline data to anticipate the incidence and type of complications following acute spinal cord injury.
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Target populations for first-in-human embryonic stem cell research in spinal cord injury. Cell Stem Cell 2011; 8:476–478.
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