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Clinical Trial
, 2015, 630932

Clinical Trial of Human Fetal Brain-Derived Neural Stem/Progenitor Cell Transplantation in Patients With Traumatic Cervical Spinal Cord Injury

Affiliations
Clinical Trial

Clinical Trial of Human Fetal Brain-Derived Neural Stem/Progenitor Cell Transplantation in Patients With Traumatic Cervical Spinal Cord Injury

Ji Cheol Shin et al. Neural Plast.

Abstract

In a phase I/IIa open-label and nonrandomized controlled clinical trial, we sought to assess the safety and neurological effects of human neural stem/progenitor cells (hNSPCs) transplanted into the injured cord after traumatic cervical spinal cord injury (SCI). Of 19 treated subjects, 17 were sensorimotor complete and 2 were motor complete and sensory incomplete. hNSPCs derived from the fetal telencephalon were grown as neurospheres and transplanted into the cord. In the control group, who did not receive cell implantation but were otherwise closely matched with the transplantation group, 15 patients with traumatic cervical SCI were included. At 1 year after cell transplantation, there was no evidence of cord damage, syrinx or tumor formation, neurological deterioration, and exacerbating neuropathic pain or spasticity. The American Spinal Injury Association Impairment Scale (AIS) grade improved in 5 of 19 transplanted patients, 2 (A → C), 1 (A → B), and 2 (B → D), whereas only one patient in the control group showed improvement (A → B). Improvements included increased motor scores, recovery of motor levels, and responses to electrophysiological studies in the transplantation group. Therefore, the transplantation of hNSPCs into cervical SCI is safe and well-tolerated and is of modest neurological benefit up to 1 year after transplants. This trial is registered with Clinical Research Information Service (CRIS), Registration Number: KCT0000879.

Figures

Figure 1
Figure 1
Visual analog scores (VAS).
Figure 2
Figure 2
Percentage of individuals converting from sensorimotor complete (AIS-A) to incomplete cervical SCI (AIS-B or AIS-C) in the transplantation and control groups.
Figure 3
Figure 3
Changes in motor and sensory score over time in patients with complete cervical SCI following hNSPC transplantation. The cervical cohort of patients was followed for 1 year. The mean (mean ± SEM) change in AMS, ASS-P, and ASS-L is shown at each time point (before transplantation (before Tx) and 2, 6, and 12 months after transplantation).
Figure 4
Figure 4
Proportion of AIS-A SCI individuals with initial C4–C7 (a) or C5–C7 (b) motor level remaining stable or gaining motor levels from the baseline to 1-year follow-up in the transplantation and control groups. The cervical motor level is indicated separately in the right and left sides of the cord. The percentage of individuals in each category of motor level change or stability at 1 year after the baseline assessment in both groups is displayed in each bar graph.
Figure 5
Figure 5
Sagittal T2W MRI scan of two SCI patients (upper panel: patient 8; lower panel: patient 15) at the time of injury (a, d), before transplantation as a baseline (b, e), and 1 year after transplantation (c, f). Follow-up findings showed progressive myelomalacic change at the site of cell transplantation (c) or myelomalacia and atrophy of the cord (f) in cell implantation areas. The white arrows mark the site of injury.
Figure 6
Figure 6
Direct transplantation of hNSPCs into the injured thoracic spinal cord (T9) of adult Sprague-Dawley rats with contusive SCI showed robust long-term engraftment and extensive migration of donor-derived cells and induced host axonal growth along engrafted cells. At 12 weeks after transplantation, immunohistochemistry was conducted in the sectioned spinal cord tissues using anti-human nuclei marker (hNuc) and anti-NF and visualized with fluorescein or Texas red-labeled secondary antibodies. Many hNuc-positive cells (colored red) survived and migrated extensively to rostral and caudal parts of the injury site, including the spared tissue surrounding the lesion. Multiple neuronal processes expressing NF (colored green) extended over the engrafted human cells, as indicated by arrows. Scale bar: 200 μm.
Figure 7
Figure 7
Human NSPCs express diverse trophic factors. (a) In vitro, proliferating (Prol) and differentiated (Diff) hNSPCs, respectively, expressed FGF2, GDNF, VEGF, and neurotrophins including BDNF, NT3, NTF4, and NGF. (b) hNSPCs notably secreted BDNF, NT3, NT4/5, NGF, and VEGF into the cultured media, compared to human foreskin fibroblasts (Fib).

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