1. Objectives
Stem cell therapy for cerebral palsy (CP) has been investigated for more than 10 years as an alternative therapeutic modality seeking cure for brain pathology which cannot be approached via conventional therapies including rehabilitation. As public interests for cell therapy increase, experimental researches continue to find ideal cell therapy which is yet proven to be effective in general. Umbilical cord blood (UCB) is considered as a safe source of cell therapy. Although autologous UCB would be ideal for this purpose, many children with CP do not have their own UCB banked which makes the allogeneic UCB an alternative for clinical application.
In a previous study, CP children treated with allogeneic UCB and erythropoietin (EPO) showed higher improvements in motor and cognitive aspects. In addition, UCB alone provided enhancement in motor function with the evidence of immunomodulation.
This 2 x 2 study aimed to measure the synergistic effects of UCB and EPO in children with CP.
2. Materials and Methods
The inclusion criteria were as follows: 1) a diagnosis of CP, 2) age between 10 months and 6 years, 3) appropriate UCB units, 4) written informed consents from parents. Participants were randomly assigned to four groups: UCB+EPO, UCB, EPO, and control groups. Brain MRI and FDG-PET scan were reassessed one year after the procedure.
Allogeneic UCB units matching at least four of six human leukocyte antigen (HLA) types A, B, and DRB1 were selected if total nucleated cells were more than or equal to 3×107cells/kg. A single infusion of UCB or placebo UCB was delivered intravenously. The UCB+EPO and UCB groups received oral cyclosporine. All participants in the UCB+EPO and the EPO groups received EPO six times every three other days at a dose of 500 IU/kg.
For a double-blind trial, placebo materials of UCB, EPO, and cyclosporine were used. Once enrolled, all participants were followed up for at least 12 months to monitor any adverse events.
Primary outcomes are changes of Gross Motor Function Measure (GMFM), Gross Motor Performance Measure (GMPM), Bayley Scales of Infant Development II (BSID-II) mental and motor raw scales. Those outcomes were assessed 5 times at baseline, 1, 3, 6 and 12 months post-intervention. Any adverse events had been monitored for 12 months.
3. Results
There were no differences of age of participation, gestational age, and baseline motor and mental scales among four groups (Table 1). UCB+EPO group showed significant improvements in post-therapy GMPM at 1 month (p=0.034) and 12 months (p=0.037) (Fig. 1). In safety, ten serious adverse events were reported, all of which were resolved without group difference. Regarding HLA disparity, more HLA-matched UCB presented better improvement of post-therapy GMFM at 1 month (p=0.036) and 3 months (p=0.050) (Fig. 2).
4. Conclusion
These results suggest that UCB therapy combined with EPO is feasible and effective for motor improvement in children with CP. |
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Fig. 1. Change of GMPM between groups the change of GMPM scores from baseline showed significant difference between UCB+EPO and Control group at post-UCB 1 month and 12 month. *P<0.05, based on Kruskal Wallis test, post-hoc analysis
Fig. 2. Change of GMFM in UCB+EPO group based on HLA disparity the change of GMFM scores from baseline was significantly greater in full matched or 1 mismatched group than 2 mismatched group in UCB+EPO group. *P<0.05, based on Mann-Whitney U-test
Values are numbers unless otherwise noted. All baseline characteristics did not show differences between the three groups (p>.05 for all comparisons). aUCB+EPO group (n=22) received UCB and EPO. bUCB group (n=24) received UCB and placebo EPO. cEPO group (n=20) received placebo UCB and EPO cControl group (n=22) received placebo UCB and placebo EPO. All groups received conventional rehabilitation during the trial dCorrected age for preterm birth eNBW was defined as birth body weight ≥2,500g, LBW < 2,500g, VLBW <1,500g, and ELBW < 1,000g. fTypology was divided as following: SB, SU, D, C, and A. Abbreviations: UCB, umbilical cord blood; EPO: erythropoietin; NBW, normal birth weight; LBW, low birth weight; VLBW, very low birth weight; ELBW, extremely low birth weight; SB, spastic bilateral; SU, spastic unilateral; D, dystonic; C, choreoathetoid; A, ataxic; PVL, periventricular leukomalacia
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