- Because limited substrate for neural repair is a significant obstacle following SCI, cell-replacement strategies are believed to be among the most promising new strategies for treating SCI. Various cell types have been tried with varying goals. Some researchers aim to produce new neurons that will integrate into functional circuits, whereas others have sought and achieved oligodendrocyte differentiation and remyelination. Despite diverse strategies, functional benefit has been consistently seen, although as yet the magnitude of this benefit has been uniformly modest.
- The ProCord trials are noteworthy for being the first human trials of cellular transplantation for SCI. The basis for this approach comes from work by Michal Schwartz in the 1990s demonstrating that autologous macrophages activated ex vivo by peripheral myelin could promote functional recovery when injected into an animal model of SCI. Possible mechanisms of action include augmented clearance of myelin debris, enhanced synthesis of beneficial trophic factors interleukin-1β (IL-1β) and brain-derived neurotrophic factor (BDNF), and decreased synthesis of the harmful factor TNF-α.
- On the basis of these results, the technology was commercialized by Proneuron Biotechnologics, Inc. (New York), and two clinical trials for human SCI were launched. The first enrolled eight patients with complete SCI, and the subjects underwent transplantation within 14 days of injury. The results of this initial study, published in 2005, reported that three of the patients, who had ASIA Impairment Scale grade A SCI, recovered to ASIA grade C status, and no major adverse events related to the cell transplants were encountered. This encouraging result led to the subsequent multicenter phase 2 ProCord trial in Israel and the United States, which included a control group. The trial was suspended prematurely in the spring of 2006 for financial reasons. Fortunately the results of this incomplete trial have now been published. They suggested harm related to autologous macrophage transplantation that was nearly statistically significant in comparison with data from a nontransplanted control group ( P = .053 for ASIA grade improvement). The numbers of adverse events were, however, no different between the two groups ( P = .942).
- Schwann cells, the myelinating cells of the PNS, are believed to be permissive of regeneration similar to that of the peripheral nerve grafts employed by Richardson and colleagues. Another potential benefit of these cells is their ability to be harvested from an autologous source, such as the sural nerve, negating the need for immunosuppression following transplantation. The work of Dr. Bunge and colleagues at the Miami Project has explored putative benefits of Schwann cell transplantation for SCI since the early 1990s. A limitation of this technique appears to be that even though regenerating CNS axons readily grow into the permissive environment that these cells provide, the axons are not prone to growing out of the cells and back into the hostile CNS environment. Nonetheless, a phase 1 clinical trial assessing the safety of autologous Schwann cell transplantation for human SCI has been initiated at the Miami Project (NCT01739023). This study will enroll patients strictly within 7 days of a complete SCI.
- Olfactory ensheathing cells (OECs) are specialized glia of the olfactory system that escort regenerating axons of olfactory receptor neurons from the PNS of the nasal epithelium to the “hostile” CNS of the olfactory bulb. This property has made them of interest to scientists given that may address the “PNS to CNS” barrier inherent in Schwann cells. Promising preclinical data exploring their transplantation for SCI have been mixed with concern that the observed benefit may actually result from remyelination by Schwann cells that contaminate OEC cultures and also bear the p75 marker.
- A high-quality human study of OECs was completed by physicians affiliated with Griffith University in Brisbane, Australia. They conducted a single-blind trial in which “purified” autologous OECs were transplanted into three patients with complete thoracic SCI within 6 to 32 months of injury. Comparison was made with matched but nontransplanted controls. Three-year follow-up data showed no motor improvement but also an absence of surgical complications.
- A Polish group reported a phase 1 study assessing the safety and feasibility of transplanting OECs and fibroblasts into three patients with complete SCI more than 6 months after injury. Comparison was made with three nontransplanted controls; rehabilitation was co-administered. The investigators reported neurological improvement in all of the patients with one moving to ASIA Impairment Scale grade B and another to grade C by 12 months after the procedure. Notably, improvements were noted on diffusion tensor imaging MRI as well as neurophysiologic parameters. No adverse effects, such as neuropathic pain, were seen. The investigators correctly stated that few conclusions should be drawn from this small study.
- OEC transplantation for human SCI was also performed in an uncontrolled Portuguese pilot study. Seven patients with ASIA grade A SCI were treated with autologous olfactory mucosal implants at 6 months to 6.5 years after injury. Apparently, all patients had improvement in ASIA motor scores, with two progressing from ASIA grade A to grade C. Additionally, two patients reported return of sensation in their bladders, and one regained voluntary anal sphincter contraction.
- China has the world's largest experience with a cell transplantation approach for SCI. A group led by Huang transplanted olfactory tissue from aborted fetuses into the spinal cords of more than 300 patients, but unfortunately the selection of patients, the acquisition and characterization of the transplanted tissue, and the outcome evaluation lacked scientific methodology. Later a group in Luongyang reported transplanting OECs into chronically injured human spinal cords twice weekly for 4 weeks in an uncontrolled study of eight patients. “Substantial” sensorimotor improvement was reported in three patients. Another group in Beijing reported modest neurological improvement in 11 patients transplanted according to Huang's protocol.
- Bone marrow stromal cells (BMSCs) migrate to the site of CNS injury following intravascular or intrathecal administration, albeit at a low rate. Importantly, they can also be transplanted in autologous fashion like Schwann cells and OECs. Many authorities believe that these cells may elaborate beneficial trophins into tissue, although numerous other mechanisms of action are possible. A number of groups are currently transplanting BMSCs into the injured spinal cords of human patients and are reporting benefit. These claims of neurological efficacy need to be interpreted very cautiously because the trials are small and generally have been conducted without controls or blinded observers.
- A Korean group has reported the results of autologous human BMSC transplantation combined with administration of granulocyte-macrophage colony-stimulating factor (GM-CSF) in a phase 1/2 open-label, nonrandomized study. This trial involved 35 patients with ASIA grade A status who underwent transplantation within 14 days (n = 17; acute), between 14 days and 8 weeks (n = 6; subacute), or more than 8 weeks (n = 12; chronic) after injury; 13 control patients were treated with decompression and fusion only. This treatment led to improved neurological function in 30.4% of patients in the acute and subacute groups, but no significant improvement was observed in the chronic group.
- Investigators in Prague have also studied BMSCs in humans. Their trial involved 20 patients with complete SCI who underwent transplantation 10 to 467 days after injury. Improvement in motor and/or sensory functions was noted in 5 of the 7 patients with acute (10-30 days after injury) SCI and in 1 of 13 patients with chronic (2-17 months after injury) SCI, leading the researchers to suggest a therapeutic window of 3 to 4 weeks following injury.
- An Egyptian group co-administered BMSCs along with sural nerve grafts and a chitosan-laminin paste in 14 patients with chronic SCI. This interesting combinatorial approach yielded an improvement in ASIA Impairment Scale grade in all patients, with 12 experiencing improvement to grade C, although the trial was uncontrolled and no patient regained the ability to stand.
- A study from Iran reported on co-administration of bone marrow stromal cells with Schwann cells to patients with chronic SCI. Negligible benefit was noted at a mean follow-up of 24 months after transplantation. Also observed was an absence of anomalies on MRI. A nonrandomized but controlled trial of BMSC transplantation into subacutely injured human patients via lumbar puncture and intrathecal infusion was performed also in Iran. A trend toward significant improvement was seen in treated patients in comparison with controls. No adverse events were seen in either the study or the control group in this trial.
- A group in Beijing reported transplantation of human umbilical cord mesenchymal cells into the injured spinal cords of 22 patients in an uncontrolled trial. It is uncertain whether their injuries were acute or chronic. Patients received one to three courses of transplantation and the duration of follow-up was 3 months to 3 years. Benefit was reported in 13 of the 22 patients; 81% of patients with incomplete injuries showed benefit. No treatment-related adverse events were seen.
- A similar study involving BMSC infusion via lumbar puncture was conducted in Japan and published in 2012. The subjects were patients with ASIA grade A acute tetraplegia. Cells were harvested during spinal fusion surgery. Patients were monitored for up to 4 years after transplantation. No adverse events were seen, and “remarkable” improvement was observed in those with initially incomplete injuries.
- Researchers at the University of California, Irvine, have reported extensively on the transplantation of oligodendrocyte progenitor cells derived from human embryonic stem cells in a rodent model of SCI. Transplantation of these cells achieves remyelination of spared, demyelinated spinal cord axons, and the observation of tissue sparing has suggested an additional neuroprotective effect. To facilitate translation, the laboratory developed a technique to ensure high purity of the cell isolates as well as techniques for culturing the cells without feeder cells, use of which could otherwise lead to viral contamination or nonhuman polysaccharide epitopes on the surfaces of transplanted cells. This work allowed Geron Corporation (Menlo Park, CA) to initiate a phase 1 human clinical trial with this cell type. For ethical reasons the trial enrolled patients with ASIA Impairment Scale grade A SCI. Unfortunately these patients have limited capacity for recovery, so the chances that this trial would show a benefit were very low. A substantial additional financial investment would be required before such an effect could be seen. Geron thus enrolled only a small number of patients in this landmark trial prior to its cessation. The technology and intellectual property were purchased by Asterias Biotherapeutics, Inc. (Fremont, CA), which completed the planned enrollment of five patients in the phase 1 trial in July of 2013. We anxiously await the results of 1-year follow-up data from this trial and word on a phase 2 trial.
- Several additional human trials of human stem and neural progenitor cells are ongoing or planned. A trial being conducted by StemCells, Inc. (Newark, CA), is performing transplantation in patients with subacute thoracic SCI a minimum of 6 weeks after injury (NCT01321333). This phase 1/2 trial was initiated in 2011 and seeks to enroll 12 patients. A second trial by StemCells, Inc., began to enroll 52 patients with cervical SCI in a phase 2 trial beginning in August 2014 (NCT02163876). The study is single-blind and randomly allocates patients to treatment or no treatment a minimum of 12 weeks after their injuries. Another phase 1/2 trial involving the transplantation of human neural stem cells 3 to 12 months after SCI is being conducted by the University of Zurich, and we await its details.
- The SCI field is advancing rapidly and novel insights are being paired with lessons learned from a generation of unsuccessful human clinical trials. Several promising therapeutics are being investigated in new studies, and the possibility that at least one of these treatments will be of benefit in SCI is high. Although an outright cure is unlikely, there is reason for researchers, clinicians, and patients to be optimistic. Neurosurgeons are on the forefront of many of these advances and may soon be called upon to be practitioners of regenerative medicine.