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Randomized Controlled Trial
. 2012 Nov;135(Pt 11):3227-37.
doi: 10.1093/brain/aws268.

Autologous olfactory mucosal cell transplants in clinical spinal cord injury: a randomized double-blinded trial in a canine translational model

Nicolas Granger  1 , Helen Blamires, Robin J M Franklin, Nick D Jeffery
Affiliations
Randomized Controlled Trial

Autologous olfactory mucosal cell transplants in clinical spinal cord injury: a randomized double-blinded trial in a canine translational model

Nicolas Granger et al. Brain. 2012 Nov.

Abstract

This study was designed to determine whether an intervention proven effective in the laboratory to ameliorate the effects of experimental spinal cord injury could provide sufficient benefit to be of value to clinical cases. Intraspinal olfactory ensheathing cell transplantation improves locomotor outcome after spinal cord injury in 'proof of principle' experiments in rodents, suggesting the possibility of efficacy in human patients. However, laboratory animal spinal cord injury cannot accurately model the inherent heterogeneity of clinical patient cohorts, nor are all aspects of their spinal cord function readily amenable to objective evaluation. Here, we measured the effects of intraspinal transplantation of cells derived from olfactory mucosal cultures (containing a mean of ~50% olfactory ensheathing cells) in a population of spinal cord-injured companion dogs that accurately model many of the potential obstacles involved in transition from laboratory to clinic. Dogs with severe chronic thoracolumbar spinal cord injuries (equivalent to ASIA grade 'A' human patients at ~12 months after injury) were entered into a randomized double-blinded clinical trial in which they were allocated to receive either intraspinal autologous cells derived from olfactory mucosal cultures or injection of cell transport medium alone. Recipients of olfactory mucosal cell transplants gained significantly better fore-hind coordination than those dogs receiving cell transport medium alone. There were no significant differences in outcome between treatment groups in measures of long tract functionality. We conclude that intraspinal olfactory mucosal cell transplantation improves communication across the damaged region of the injured spinal cord, even in chronically injured individuals. However, we find no evidence for concomitant improvement in long tract function.

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Figures

Figure 1
Figure 1
Flow chart to summarize patient recruitment, assessment and follow-up. OMC = olfactory mucosal cell.
Figure 2
Figure 2
Flow chart to illustrate trial design. (A) Trial dogs were recruited from the population of companion dogs that had incurred severe spinal cord injury at least 3 months previously and had not regained behavioural evidence of pain perception from the hindlimbs or voluntary hindlimb locomotor function or urinary continence. They were randomly allocated to receive olfactory mucosal cells (OMCs) or cell transport medium alone in a 2:1 ratio. (B) Olfactory mucosa was harvested from each dog and olfactory mucosal cells were multiplied in culture for ∼3 weeks, aiming for a total population of ∼5 × 106 cells containing ∼50% olfactory ensheathing cells (defined as p75+ by immunocytochemistry) before transplantation—values stated here are mean ± SEM of the cell population among all 34 dogs. (C) Each dog received an intraspinal transplant of either autologous olfactory mucosal cells or cell culture medium alone. Transplants were injected percutaneously, using fluoroscopic guidance to ensure correct needle placement. (D) A blinded observer assessed outcome at monthly intervals for 6 months after intervention. Each test and statistical analysis method was pre-specified to avoid biased analysis; the primary outcome measure was objective quantification of forelimb–hindlimb temporal coordination using computerized analysis of digitized kinematic data. SSEP = somatosensory-evoked potential; TMMEP = transcranial magnetic motor-evoked potential.
Figure 3
Figure 3
Digital recordings of locomotor activity can be represented by sine wave patterns, here corresponding to forward and backward motion of the paws during walking on a treadmill. In this series of wave patterns, corresponding to video recordings of Dog 8 in Supplementary Fig. 2, the fore paw movement is shown by the dark and light green traces and the hind paw movement by the red and blue traces. The generation of the sine wave pattern is illustrated in A, illustrating the correspondence between forward and backward motion of the paw during treadmill walking (the oval shape on the image in A) and the wave pattern. Temporal coordination between forelimb and hindlimb motion is then analysed using a MATLAB script to determine the time interval between the peaks of the ‘sine wave’ patterns (red lines between the curves in B, C and D), corresponding to the furthest extent of each step by each limb. Pre-transplantation in Dog 8 (A), there are only occasional stepping movements in the hindlimb and this is reflected in the very high ‘coordination score’ (here = 2.71), which is a summation of the ‘lag’ between corresponding forelimb and hindlimb movements. At 1 month (B) and 6 months (C), the same dog shows more regular hindlimb stepping, and overall coordination is improved but imperfect; there still remains an increasing ‘lag’ time between corresponding fore paw and hind paw placement during the recording period (the ‘coordination score’ is 1.21 in B and 0.78 in C). In D, Dog 30 illustrates a return of near-normal coordination between fore paw and hind paw placement after transplantation of olfactory mucosal cells 6 months previously (the ‘coordination score’ = 0.26). In this panel, there are prolonged periods of regularity in the time interval between fore paw and hind paw placement, as occurs in normal dogs, interspersed with periods in which coordination between limb girdles is lost.
Figure 4
Figure 4
Analysis of effect of intraspinal injection of olfactory mucosal cells (OMC, blue) compared with cell transport medium alone (NC, red) on measures of forelimb–hindlimb coordination (A) and spinal cord long tract function (B–E). (A) Linear regression plot of fore–hind coordination scores during the 6-month trial period (low scores indicate good performance). *The sum effect of olfactory mucosal cell transplantation compared with the no-cell group, when controlling for the effects of time and baseline scores, was highly significant (β = −0.455; P = 0.007). (B) Linear regression plot of lateral stability ratio scores during the 6-month trial period (low scores indicate poor performance). The scores did not differ between the olfactory mucosal cell and no-cell groups (β = 0.049; P = 0.428). In A and B, solid lines indicate linear relationships and dashed lines indicate 95% confidence intervals. (C) Latencies of transcranial magnetic motor-evoked potentials recorded before and 6 months after intervention and adjusted for individual dog size (each symbol represents a single individual). There was no difference in recovery incidence (Fisher exact test P = 1.00) or final latencies (P = 0.544, Mann–Whitney test) between the olfactory mucosal cell and no-cell groups. (D) Latencies of recorded somatosensory-evoked potentials before and 6 months after intervention adjusted for individual dog size (each symbol represents a single individual). There was no difference in recovery incidence (P = 1.00, Fisher exact test) or final latencies (P = 0.788, Mann–Whitney test) between the olfactory mucosal cell and no-cell groups. In C and D, lines indicate mean and SEM. (E) Bladder compliance measures recorded before and 6 months after intervention. There was no difference in compliance between the olfactory mucosal cell and no-cell groups during the trial period (β = −0.077; P = 0.852; multivariable regression analysis). Bars indicate mean, lines indicate SEM.
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